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Yale BIDS Xu Lab 41

in the absence of sorl1 app fails to be transported out of the endosome and this leads to an increase in generation of aβ in induced pluripotent stem cell ipscderived neurons loss of sorl1 leads to impaired endosomal trafficking and autophagy and ultimately increased aβ levels consistent with these findings loss of sorl1 in ad mouse models leads to an increase in aβ levels in the brain

[16174740 27638701 32492427 34133918 19036982]

singlenucleotide polymorphisms snps at the sorl1 locus are associated with ad in genomewide association studies gwass importantly several sorl1 coding variants have been identified in a subset of patients with earlyonset alzheimers disease eoad and variants leading to premature termination codons are found exclusively in alzheimers disease ad cases further reduced expression of sorl1 has been observed in the cerebrospinal fluid csf and postmortem brain of individuals with lateonset ad together these data suggest that sorl1 plays a causal role in ad sorl1 has a major role in intracellular trafficking of various cargos including amyloid precursor protein app which is mediated in part through its role in retromer complexmediated trafficking reviewed in small and gandy

[24162737 35379992 30009200 28537274 15313836 19364929 33667416 17015224]

the first compound quercetin is found to have antiinflammatory antiobesity and cardioprotective action in cardiovascular diseases 53 and antioxidant properties 54 antiarthritic effect 55 antihypertensive effect 56 anticancer properties 57 antidiabetic effects 57 antiallergic effects and so on

[34101925 29966915 28342364 19307694 27589790 27589790 34101925]

this study reveals the high affinity of quercetin and myricetin towards ache as depicted by their binding energies of -10.6 and -10.5 kcal/mol, respectively, as well as alpha-amyrin and beta-chlorogenin towards buche as depicted by their binding energies of -12.1 and -11.2 kcal/mol, respectively. in contrast, the donepezil revealed the affinity -7.6 kcal/mol with ache protein and -9.8 kcal/mol with buche protein which indicates the lower affinity than spice plant phytochemicals.

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extracellular circulating mirnas have been investigated as potential biomarkers for ad diagnosis in various studies given their recognized significance in neuronal function and survival

[31659197 36835108 29738527 24827165 36941055]

to date, in tear fluid, approximately 300 different mirnas have been isolated. among these some are newly discovered and their regulatory roles remain relatively unexplored

[31659197 36835108]

since then replicative senescence has also been reported in vivo across different mammalian species ranging from the proliferating cells of embryonic tissues 38 92 to many of those in adults including endothelial cells 93 lymphocytes 94 and vascular smooth muscle cells

[24238962 24238961 31109450 18164586 26416809]

cellular senescence was first described in the 1960s by leonard hayflick and paul moorhead as the irreversible proliferative arrest of fibroblasts following prolonged culturing in dishes this phenomenon is later known as replicative senescence and has become a major focus in the field of biogerontology

[28688962]

the excessive deposition of extracellular aβ is often not accompanied by ad

[ 2897823 2259457 19001171 21280088 33926499]

the mutations of the former lead to the pathological formation of tau tangles and the disease the reverse does not occur the correlation between levels of extracellular aβ and ad is poor athe excessive deposition of extracellular aβ is often not accompanied by ad 13141516171819bthe occurrence of ad as judged by cognitive symptoms as well as by pet scan and postmortem analysis is not always accompanied by excessive deposition of extracellular aβ

[25307057 2897823 2259457 19001171 21280088 33926499]

based on the cholinergic hypothesis of ad the reduced ach levels in the brain and deficits in central cholinergic neurotransmission lead to cognitive impairment which is the main clinical symptom of ad two enzymes are involved in hydrolysis of ach which are butyrylcholinesterase bche and ache and the ache activity is markedly increased in the ad brain ache inhibitors acheis increase the level of ach in the brain and therefore they improve learning and memory and attenuate cognition impairment donepezil is a reversible achei that demonstrates high selectivity toward ache inhibition compared with bche and it has a long duration of action donepezil inhibits ache stimulates nicotinic acetylcholine receptors and prevents cholinergic degeneration which is associated with enhanced synaptic strengthening that is related to cognitive function improvement and reduced spatial memory impairment

[28102474 31773661 18265960 29463072 22114680]

group treated with dpl/ast–solution (ache; 13.70 ± 0.78, 14.29 ± 1.36 ng/mg protein, ach; 15.32 ± 0.65, 18.73 ± 0.91 pg/mg protein) showed similar results to dpl–nlcs, with no significant difference between them in cholinergic parameters. group treated with dpl/ast–nlcs showed significantly lower ache levels (8.13 ± 0.96, 8.76 ± 1.82 ng/mg protein) and significantly higher ach levels (22.17 ± 1.50, 32.90 ± 1.61 pg/mg protein) than the ad-like untreated rats and groups treated with dpl–nlcs, dpl/ast–solution, or dpl–solution in the cortex and hippocampus, and also treatment with dpl/ast–nlcs completely normalized the levels of ache and ach in the cortex and hippocampus.

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various reports including some from our research group have demonstrated beneficial disease modifying effects of ga in adlike mouse models

[33090673 28860067 34744620 26284939 26049087]

these data support the hypothesis that ga treatment does not increase dam found within the vicinity of 6e10+ aβ plaques. due to its ability to induce type 2 responses and its excellent safety profile ga has been one of the candidate therapeutics of interest for repurposed use in ad

[35563884]

the 808 nm nir wavelength was chosen for this study because it is at the absorption peak of the primary photoacceptor cco 4791 has optimal penetration through the skull 222324 and has proven effects on cbf 90 and on cognition

[15557336 26346298 23077622 25772014 28186867]

the t-pbm-2.0 device operates in one of five modes: nir continuous low irradiance (50 mw/cm2), nir continuous middle irradiance (300 mw/cm2), nir pulsed middle irradiance (300 mw/cm2), nir continuous high irradiance (700 mw/cm2), and sham. since the proposed average irradiance dose of tpbm at 300 mwcm2 is the most frequently used dose reported in the literature 89 and has been associated with changes in cbf 90 and cognition for this study we will only employ the nir pulsed middle irradiance 300 mwcm2 and sham modes at 42 hz with a pulsing 33 duty cycle

[34487045 28186867]

in addition the aβ40 peptide is preferentially associated with vascular deposits and caa in the human brain resulting in degenerative phenotypes in cerebral endothelial cells31 which culminate in vessel wall dysfunction57 58 contributing to bbb permeability and microhemorrhages

[33155752 19770225 22695614 24670400 34867298]

This cardiac maladaptive remodeling is accompanied by a significant accumulation of Aβ, particularly Aβ40, colocalized in perivascular and interstitial spaces with collagen deposits, as well as caspase 3 activation in cardiomyocytes, suggesting that Aβ deposition in the heart tissue contributes to the development of interstitial fibrosis and apoptotic cardiac cell death (Fig. 2). the preferential accumulation of aβ40 rather than aβ42 in tg2576 mice hearts is in line with previous studies describing the progressive increase mostly of aβ40 levels in both serum and brain parenchyma of tg2576 mice during aging

[11160418]

interested readers can refer to review papers eg for the intricacies of the mechanism

[27274215 25113539 32429229 28781776 31556570]

one reason for this is that the progression of alzheimer’s disease is regulated by a large number of genes, reactions, and pathways which are still under investigation. this work does not aim to illustrate the detail of all genes/pathways known for their involvement in alzheimer’s disease.

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the rapidly increasing number of studies demonstrates the importance of the ldrsb in resistance to ad pathology and suggests that the development of methods for augmentation of the ldrsb functions may contribute to strong progress in the therapy of ad

[34943796 31452991 32878058 36834631 30046111]

since the treatment of ad is incurable, therapy aimed at reducing the progression of the disease should be applied throughout the life of patients. in this respect pbm technologies are the most promising since they are already widely used in the clinical field for the treatment of various brain diseases

[36061601 29131369 37041790]

yu et al suggested that rbck1 promoted the ubiquitination and degradation of p53 the impairment of p53 expression and activity might participate in neurodegeneration as p53 can bind to genes that regulate expression of synaptic proteins neurite outgrowth and axonal regeneration which indicated a neuroprotective role against ad development in addition rbck1 can regulate the proinflammatorycytokinesinduced nuclear factor kappa b nfkb activation which serves as a pivotal mediator of inflammatory responses nfkb activation is a common feature of many neurodegenerative diseases and the increased expression andor activation of nfkb has been largely observed in postmortem studies of ad patients however the two cpg sites were not found to be associated with any neuropathology markers in the current analysis

[30874541 29733887 27382069 25652642 27881951]

scarce evidence related to air pollution has been reported on cg25433380. higher dna methylation levels of cg10495669 in nasal cells have been associated with 1year ambient pm25 exposure among 503 children in massachusetts rbck1 the gene which cg10495669 is assigned to is involved in carcinogenesis and inflammation pathways

[33872926]

ad is neuropathologically characterized by the presence of extracellular βamyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein wnt signaling participates in multiple aspects of cellular function and contributes to synapse formation synaptic activity and neurogenesis in the brain and dysfunction of wnt signaling may aggravate the pathogenesis and progression of ad

[33667416 28624530 29967987 32616667 31191253]

upregulation of wnt2b exerts neuroprotective effect by alleviating mitochondrial dysfunction in alzheimer's disease alzheimer disease (ad) is the most common neurodegenerative disorder leading to dementia in the elderly worldwide.

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wnt2b has been studied in cancers or tumorrelated diseases while wnt2b is one of the most important components that can induce the particular developing pattern of the fetal hippocampus and related to neurogenesis such as retinal ganglion cells interestingly wnt2b is also characterized as a mitochondriaexpressed protein which shuttles between mitochondria and the nucleus however wnt2b has not been studied in ad particularly since it is expressed in mitochondria unlike other wnt family members

[32826863 12271469 21856951 27438855 25356045]

ad is neuropathologically characterized by the presence of extracellular βamyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein wnt signaling participates in multiple aspects of cellular function and contributes to synapse formation synaptic activity and neurogenesis in the brain and dysfunction of wnt signaling may aggravate the pathogenesis and progression of ad we have been focusing on the research and development of blood and cerebrospinal fluid csf markers that can be used for early diagnosis of ad and we have found a variety of proteins that were significantly different in the blood and csf of ad patients and cognitively normal subjects recently we found that wnt2b a member of wnt family in the plasma of ad patients are lower than in healthy controls

[33667416 28624530 29967987 32616667 31191253 32776690 34044860]

in common spatial reference memory test the mwm a wide variety of different protocols are used across studies in congenic 5xfad mice generating divergent data

[29548672 29288735 27542275 27453234 29427384]

a recent deep phenotyping study found no deficits in 5xfads compared to wt controls at 6 or 12 months of age in the ymaze while other studies found deficits at 6 9 and 12 months of age but not 3 months in the cross maze or at 7 11 and 18 months of age but not 3 months in the ymaze others have also noted deficits in spontaneous alternation as late as 10 months of age

[27453234 29548672]

genomewide association studies gwas identified many ad risk genes related to the immune response and microglia including the phagocytic receptors cd33 and trem2

[18976728 21460840 21460841 23150934 23150908]

accumulation of amyloidbeta αβ is a defining histological hallmark of the ad brain however failures in αβtargeted clinical trials combined with findings showing no apparent correlation between cognitive decline and overall plaque load in ad patients suggest that additional mechanisms may be crucially involved in ad etiopathogenesis

[32739008 24383468]

consistent with the local activation of the amyloidogenic pathway with the generation of aβ species in these transgenic mice the intensity signal of app figure 1ab and bace1 figure 1cd was inversely increased into synaptic compartments from both tissues hippocampus p 00001 p 001 retina p 00001 p 00005 tg2576 versus wildtype

[33750467 32954296 26048669 15917100 16306400]

As shown in Figure 1E,F and regardless of the analyzed area (hippocampus versus retina), the steady state expression level of neuron-specific BIN1 isoform (65 kDa BIN1.1) was significantly reduced in Tg2576 AD mice when compared with littermate wild-type group (hippocampus **** p < 0.0001; retina *** p < 0.0005, Tg2576 versus wild-type). this finding is in line with the evidence that downregulation of bin1 is associated with poorer memory performance in ad cases 77787980 and in this preclinical ad model especially in the concomitant presence of tau neuropathology

[22539578 23226438 33398016 24205320 32719966 31263146 31408457]

thrombin cleaves fibrinogen to form fibrin monomers which polymerize to create the fibrin clot

[30323343 33252741 31011700 28101869 17664291]

another study suggested that the binding of fibrinogen and aβ in the brain may exacerbate the severity of a tgcrnd8 ad model in vivo 5556 as this association can result in the formation of abnormal blood clots and blockages in the cerebral vasculature similar to fibrinogen fibrin also plays an important role in the process of blood clotting

[20547128 33551734 30816210 20547128 30323343 33252741 31011700 28101869 17664291]

heme oxygenase exists in two isoforms heme oxygenase1 ho1 which is robustly inducible by multiple triggers that drive nrf2 expression and heme oxygenase2 ho2 which is considered to be constitutively expressed and modestly inducible by few factors

[10602774 12736340 16459095 25761244 16371440]

regardless the antioxidant and antiinflammatory effects from enzyme activation through the nrf2 pathway have the potential to counteract damage from sustained microglial activation One of the important pathways activated by NRF-2 is the heme oxygenase 1 (HO-1) pathway, which is outlined in Figure 1.

[36316319]

for example hypericin can reduce cytokineelicited activation of both stat1 and nfκb in a dosedependent manner it is also able to mediate the activation of the camppkaampk pathway caused by highfatdietinduced metabolic abnormalities further hypericin and other bioactive components in the extract from hypericum humifusum may inhibit acetylcholinesterase and some key enzymes linked to t2d or downregulate homeobox1 pdx1 expression and erk activity in addition hypericin is found to be an effective inhibitor of αglucosidase a major enzyme that is involved in t2d by altering its structure and microenvironment and reducing its activity

[18226577 33143088 31337977 28147885 34361714]

iapp is one of the major secretory products of pancreatic β‐cells and has the ability to aggregate into insoluble amyloid fibrils that are cytotoxic to β‐cells. due to its role in the loss and dysfunction of βcells iapp is suggested to be a therapeutic target for t2d management the deposition of iapp can affect a number of biological processes such as disrupting the structure and function of cardiac myocytes and upregulating the proinflammatory cytokine interleukin1β il1β levels consistently previous studies have identified some genes and pathways potentially involved in the effect of hypericin in preventing and treating diabetes

[36105173 21742788 27335231 32941692]

the different stage of ad models the effect of rapamycin on microglia in the brain and the side effects of rapamycin remain unexplored mtor signaling pathway is not only involved in a variety of cellular functions in the brain but is also present in many types of brain cells such as mature neurons microglia astrocytes and neural stem cells rapamycin lacks specific targeted therapeutic effects and potential side effects may occur with nonselective autophagy induction in vivo to address this issue a rapamycin formulation carried by transferrin decoratednanostructured lipid carriers rapatfnlcs was utilized to target neurons in ad lesions

[34215308 35672148 31690173 35805130 27690737]

thus, the above numerous factors influencing the experiment have led to controversy about the effect of rapamycin on ad. however, mtor signaling has complex effects on the ad brain.

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we believe that hypomethylation is the key regulatory mechanism responsible for the transcriptional changes of these genes as elevated sah levels and reduced samsah ratios have been confirmed in various experimental hhcy models by us and others

[27992360 9312159 11694601 17698632 14630804]

firstly, hhcy suppresses mg aβ phagocytosis via impaired mg aβ engulfment. secondly, hhcy promoted inflammatory response via activating nf-κb and il-1 pathways.

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in ad bbb impairments such as changes in the pericyte coverage 11 tight junction tj damage 12 and endothelial cell death 13 are considered as one of the principal causes of cerebral amyloidosis due to their essential role in clearing abundant cerebral aβ

[29453790 22745485 22615835 26005850 29377008]

caa is found in over 85 of ad patients characterized by pathological aβ deposits on blood vessels and other vascular abnormalities and it was proposed as a marker of clinical ad the development of caa indicates reduced amyloid clearance from the brain parenchyma 8 impaired amyloid transport across the endothelium and the failure of amyloid degradation

[21205781 23489283 20854368]

cognitive impairment due to ischemia is mild to severe and has been seen in approximately 3570 of survivors one year after a stroke

[22311341 23150656 24577459 31712368 37125534]

a focal ischemic episode typically damages the brain cortex, hippocampus, temporal lobe, entorhinal cortex, amygdala and parahippocampus to varying degrees. postischemia, these structures are involved in cognitive and memory deficits, and their progressive degeneration also induces behavioral changes.

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thus the presented alterations indicated that the dysregulation of the expression of autophagy and apoptotic genes may be associated with a different response of neurons in the ca1 and ca3 areas of the hippocampus and in the medial temporal lobe cortex to transient global brain ischemia

[27472881 27710863 29363901 29128811 31707369]

this overexpression was accompanied by the downregulation of caspase 3 gene 2 days after brain ischemia next on days 7 and 30 after ischemia the above gene was impressively upregulated

[27472881 27710863 29363901 27472881 27710863 29363901]

several of the critical pathogenic functions of p2x7 could be mediated by p2x7 specifically expressed on microglia including the release of il1β and chemokines and the secretion of taucontaining exosomes see previous paragraphs figure 1 and table 2

[29934546 34391810 34516970 22048123 32811520]

in general microglia exhibit the highest levels of p2x7 in the brain thus, the observed increase in p2x7 in glial cells suggests their potential contribution to the pathogenesis of ad.

[22467178 30691318]

cognitive deficits are common in patients with chronic epilepsy particularly in temporal lobe epilepsy tle and lateonset epilepsy

[33279986 33097597 28284559 31834353 32351438]

in ad patients with epileptiform activity the minimental state examination mmse score decreased faster compared to ad patients without epileptiform activity furthermore antiseizure medications asms eg levetiracetam lev decreased neuronal hyperexcitability and improved cognition in animal models and in patients with mild cognitive impairment mci and are being investigated in ongoing studies for ad

[27696483 22869752 34332638]

previous studies utilizing bisulfite sequencing or pyrosequencing have reported relatively low levels of mtdna methylation in the dloop region and the mtrnr1 gene across different human cell and tissue types with estimated levels ranging from 1 to 34

[36726473 26996456 23656717 27107129 32657220]

these findings highlight the importance of considering mtdna methylation as a potential target for further investigation in ad. the existence of methylation in mammalian mtdna remains a subject of debate.

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bdnf levels are known to fluctuate in response to factors such as age sex hormones lifestyle and stress however chronic alterations in its expression can be indicative of or potentially lead to chronic diseases such as ad

[26788077 32012942 30634650 32825341 17204313]

recently rsg formulated with nanoparticles was shown to modulate bdnf and its upstream signaling pathway substrates in models of diabetes and ad to better understand how rsg may act through this mechanism, alterations to bdnf expression and its pathological involvement in ad must be explored.

[32683650 33860663 25510319]

in the present study we conducted additional comprehensive in vitro experiments to assess a potential direct effect of dmf and its metabolite mmf on abc transporter activity a group of transporters associated with ad

[34977908 21460840 36411364 16207713 35477481]

apart from the induction models, only one publication proposed possible positive ad treatment effects of dmf. the authors used a doubletransgenic mouse model app and tau and assessed activation of nrf2signaling by dmf which led to a trend of reduced impairment of motor functions during the disease progress and improved memory through reduced neuroinflammation

[30029164]

the strong relationship with these biomarkers suggests that thop1 changes are associated with upstream and downstream mechanisms in ad such as tau pathology neurodegeneration and total aβ load despite the thop1 increases in response to aβ neurotoxicity the association between aβ42 and thop1 only in the control group suggests that thop1 may not respond to aβ fibril and plaque formation further supporting a relationship of thop1 with normal aβ physiological functioning altogether the increased thop1 concentrations detected in the mci stage and the significant correlations with ad csf biomarkers may suggest that this protein could be a useful biomarker for detecting an early neuroprotective response against ad pathology

[35026840 16602710 18571100 31431000 11559896]

this suggests that the lack of significance observed in the independent cohorts is probably due to the lower sample sizes and not to the presence of amyloid comorbid pathology in the dlb group. strong correlations between thop1 with t‐tau, p‐tau, and aβ40 concentrations in the total cohort were observed.

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most studies reported the use of antihypertensive drugs ahds in patients and controls some also reported the use of antidementia medication

[19433892 29844143 24251392 24670396 19433892 29844143 22460326]

mmse score ≤25). in addition to age, sex, and education or cognition, data on bp, medication use, bmi, and vascular risk factors or comorbidities were collected.

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others have proposed that it is a form of lysosomal storage disorder 36 or a novel form of diabetes 37 or that ad is caused by autophagic dysregulation 38 neuroimmunomodulation 39 or by excess exposure to aluminum

[31482121 19885299 35654956 20134203 21157018]

however this only overcomes some of the shortcomings of the original amyloid hypothesis another is the tau hypothesis which argues for a central role for tau protein rather than aβ in the pathogenesis of ad

[29440986 29440986 20682182]

so the hyperaccumulating aβos produce the toxic hptos that actually kill the cells and like aβos are also able to prionlike spread the clinical symptoms

[31157827 30362029 23332364 30355155 29887142]

ad is actually a terminal tauopathy in which the currently invisible toxic aβos start the connectopathy by inducing the mislocation of normal tau from the axon to the sdc by stimulating its hyperphosphorylation. this produces the unfolded toxic tau that collaborates with prpcs to destroy synapses

[28864542 30355155 30001506 31524157]

since apoe competes with reelin for apoer2 binding in model systems an excess of apoe following injury could potentially compromise reelinapoer2dab1 signaling lastly since reelinsecreting neurons are reported to degenerate in sad reelin depletion could help explain or exacerbate the hyperphosphorylation of tau as well as the accumulations of dab1 pp85αtyr607 plimk1thr508 and ppsd95thr19 observed in the present study

[10571240 10571240 17360894 27031488 31870804 10571241]

apoe particles deliver lipids that are highly vulnerable to peroxidation to neuronal apoe receptors including apoer2 our recent finding that apoe and apoer2 are vulnerable to lipid aldehydeinduced adduction and crosslinking provides a mechanistic link between lipid peroxidation and apoer2dab1 disruption since lipid peroxidation is a common feature of many sad risk factors reviewed in this mechanism could help explain previous observations that lipid peroxidation is markedly increased in the early stages of sad astrocytes stimulate repair of injured axons by dramatically increasing local secretion of lipidloaded apoe particles

[35466940 35466940 35466940 35466940 16240347 22137893 2419900 2493483]

we observed a high toc in patients with ad consistent with the evidence of cortical thinning as a consequence of ad neuropathology moreover we also observe significant associations with cortical thinning and poor cognitive performance a decrease in csf aβ and an increase in csf ptau which is also consistent with previous findings atrophy has also been associated with the risk of progression from mci to ad alongside a combination of other biomarkers importantly these previous studies examined the correlates of common patterns of cortical atrophyyet conversely we considered individual variability in patterns of cortical thickness as opposed to assessing group average relationships

[21504134 23507382 24852682 19439419 32643852]

overall, the results of the present study provide evidence of (1) heterogeneous patterns of cortical thickness between patients with ad, (2) associations of cortical thickness heterogeneity with cognitive performance and csf aβ and p-tau, and (3) the potential of individualized markers of cortical thickness heterogeneity to predict survival time before conversion from the mci stage to diagnosed ad. our findings both complement and offer additional information to the established understanding of ad.

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more and more experimental evidence including genetic 1213 and epigenetic 14 studies transcriptome analysis of brains of patients with ad 15 and expression quantitative trait experiments in monocytes supports a contributing role of innate immune mechanisms in ad

[24162737 27088644 25693568 23622250 24786080]

a previous study provided evidence that red ginseng, steamed at higher temperature and pressure, has the major components of these eight rare ginsenosides. alzheimers disease ad is neurodegenerative with various pathophysiological aspects under investigation

[30028503]

recently two independent studies reported that a heterozygous rare variant in trem2 pr47h is significantly associated with ad 2829 and multiple variants in the same gene increase ad risk

[23150934 23150908 22312439 22801501 8446617]

snps in the trem2 gene modulate protein expression 18 and function possibly resulting in an inactive receptor such single nucleotide polymorphisms snps were identified as risk factors for alzheimers disease ad a central nervous system disease that leads to dementia 19 and it is characterized by progressive cognitive dysfunction memory loss and neuroinflammation

[27995897 25732305 27995897 25792098 23979026 26939933 30406177]

the aβfe3 redox interaction mechanism has been validated in aβ amyloid plaque cores from ad postmortem and transgenic mouse brain tissues

[24671940 24559299 28890316 29688240 32587293]

our early in vitro study has first demonstrated that aβ can directly reduce fe3 to fe2 initiates the fenton reaction and engenders oxidative stress via a heightened generation of reactive oxygen species ros such as h2o2 and ho radical production we first employed synchrotronbased xray fluorescence microscopy xrfm and detected abnormal iron enrichment in procured aβ amyloid plaques from ad postmortem brain tissues using the laser capture microdissection lcm technique

[15105262 10386999 16503166]

in the literature it was shown that both ischemia and inflammation play a role in the pathophysiology of ad vitamin d and nlr were used as a biomarker for inflammation and atherosclerosis in literature

[15850663 22922667 36592816 33013672 24861877]

roc curve analysis between fazekas zero and fazekas three groups. abbreviations: ad: alzheimer’s disease. auc: area under the roc curve.

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the aβ protofibril selective monoclonal antibody mab158 3 27 was recombinantly expressed on a mouse igg2c backbone either in regular igg format or as a bispecific antibody conjugated to single chain variable fragments of the tfr binding antibody 8d3 28 scfv8d3 at the light chain ctermini as previously described resulting in rmab158scfv8d3

[17623042 20714111 9681691 28042336 28932173]

wild type wt and appnlgf mice expressing mouse amyloid precursor protein app with a humanized aβ sequence and with the swedish km670671nl arctic e693g and iberian i716f app mutations were used in the study all experimental procedures were approved by the uppsala county animal ethics board (5.8.18–13,350/2017 and 5.8.18–20,401/2020), carried out according to regulations of the swedish animal welfare agency, and complied with the european communities council directive of 22 september 2010 (2010/63/e.u.).

[24728269]

we followed the procedure described in a previous study briefly the diffusionweighted imaging data were preprocessed using fsl fmrib software library the nonbrain tissue was removed epi distortion was corrected using epibased field mapping and eddy currents and head motion were corrected

[32035186 21979382 12391568 9469719 26481672]

a b0 field map was collected with matching geometry for use in unwarping epi distortions due to magnetic field inhomogeneity the field map acquisition was performed with a 3d dualecho spoiled gradient echo pulse sequence field of view 240 240 mm matrix size 80 80 isotropic voxel size 3 mm number of slices 48 repetition time 675 ms echo time 1 492 ms echo time 2 738 ms flip angle 60 to characterize the microstructural properties of the human cholinergic system, a diffusion mri-based in vivo model was derived.

[7674900]

several studies have shown that ras is a potential contributor to dementia and ace2ang17mas1 axis has been demonstrated to be important it has been proven that in the injury models of central nervous system inducing ace2 or ang17 activation of masr signal has neuroprotective effects on neurogenic hypertension and ischemic stroke our results indicated that the activity of ang17 a critical regulator of ace2ang17mas1 pathways was decreased in the brain tissues of appps1 mice while dize remarkably increased the brain levels of ang17 and mas1

[32701063 34955647 33526381 19923158 23997755]

further high-throughput sequencing indicated that mirna-224-5p expression was drastically upregulated in astrocytes of app/ps1 mice after dize treatment, and mediated the inflammatory response through nlrp3 inflammasome. thus, this is the first study to show that dize mediated astrocyte-regulated neuroinflammatory responses via mirna-224-5p/nlrp3 pathway.

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in the adcssponsored dha trial 2 g of dha supplementation per day over 18 months was not effective in slowing cognitive decline in persons with dementia particularly among those carrying the apoe4 allele in this trial apoe4 carriers had a threefold lower increase in csf levels of epa and dha after supplementation when compared with noncarriers with the limited conversion of dha to epa possibly due to oxidation of these omega3 fatty acids in the omegad clinical trial supplementation with 23 g of dha and epa per day over 6 months in persons with mild ad was associated with an increase in markers of inflammation and neuronal injury in csf in contrast in a 12month randomized clinical trial of 327 g epa dha per day in middleaged cognitively normal individuals apoe4 carriers had the greatest increase in plasma oxylipins following highdose dha epa supplementation higher levels of these oxylipins in apoe4 carriers may help offset a metabolic and proinflammatory state

[21045096 28733268 17998483 23631810 34604280]

each predictive model had an roc auc of at least 0.824. these findings underscore the potential role of systemic lipids in driving the pathology of ad.

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er stress triggers an unfolded protein response upr and transcriptionally regulates lipogenesis 85 thus playing an essential role in lipid metabolism 85868788 3 stress damage such as dna damage and response play a major role in cellular senescence in vitro

[22195283 22195283 27146479 33398919 36499512 28688962]

interestingly, stress damage and response interlock the immune system and lipoprotein metabolism in multiple ways. some examples are 1 oxidative damage to lowdensity lipoproteins ldl is a wellknown initial step of atherosclerosis inducing inflammatory responses by releasing cytokines and chemokines 828384 2 metabolically linked proinflammatory stress such as endoplasmic reticulum er stress modulates lipid metabolism and mediates the release of cytokines il1α il6 and il8 which are known to participate in agerelated chronic inflammation

[18625445 24903093 30806246 31011483]

natural mitochondrial trafficking may transfer injured or degraded mitochondria from the cell body to synaptic terminals

[ 9096346 9115741 15377858 2469224 17696767]

to meet cellular energy requirements synaptic mitochondria are first created in the cell bodies of neurons and are then transferred from the axon or dendrite this process is referred to as mitochondrial trafficking

[ 9096346 9115741 15377858 2469224 17696767 9096346 9115741 15377858 2469224 17696767]

although reactive astroglia increases trophic support and glutamate uptake isolates lesioned areas favoring regeneration activates immune pathways and promotes bbb repair 45 46 47 astrocytes can become dysfunctional and acquire cytotoxic potential under prolonged stress

[20012068 31583588 25726916 16873533 31110130 20012068 31583588]

through the reactive response astrocytes aim to restore regional homeostasis gradually modifying their transcriptional profile and adapting their cell morphology and activity finely tuned morphological changes are driven by an increase of intermediate filament proteins such as gfap and vimentin 15 38 41 42 43 which not only provide mechanical sustenance for the maintenance of astrocyte shape but also support the functional profile of reactive astrocytes through transcriptional modulation of target genes involved in astroglial and microglial responsiveness

[29351512 20012068 29351512 20012068 18586353 28212850 31583588 25731615 25726916]

the human p2x7r gene is highly polymorphic with more than 150 nonsynonymous snps the majority of which lead to amino acid substitutions in the extracellular loop or the cytoplasmic cterminal tail 61 affecting agonist binding affinity 62 trafficking to membranes 63 ion channel activity 64 and permeability of the pore

[24928329 15123679 12586825 11150303 20360457]

in contrast to other p2x subtypes p2x7r does not undergo desensitisation after activation of the receptor due to permanent stabilization provided by a palmitoylated cysteine rich region in the cytoplasmatic domain this feature of p2x7r activation dynamics likely contributes to the hyperpolarised astrocyte membrane potential that is important for astrocyte physiology and functions

[31587896 34525325]

whilst the neuronal localization of p2x7r remains controversial 7576 p2x7r expression in astrocytes 71727780 has been confirmed by the presence of agonistinduced currents and ca2 responses

[28747388 28747389 29934546 34391810 19289154]

opening of the p2x7r channel is stimulated by atp concentrations in the higher micromolar to millimolar range in contrast to the lower atp concentrations required for opening of other p2x family members with atp4 being a true agonist atp can be sensed by p2x7rs in rodent or human microglia which show the highest levels of p2x7r expression in the brain 6972 and oligodendrocytes

[23040806 17728465 34054698]

until now there have been five antiad drugs approved by the fda namely the ache inhibitor tacrine 9 donepezil 10 rivastigmine 11 galantamine 12 and the nmda receptor antagonist memantine

[27876467 30372021 27094132 11230880 23657927]

the pathogenesis of ad is complex involving βamyloid protein deposition neurotransmitter deficiency metal metabolism imbalance overexpression of monoamine oxidase b maob neuroinflammation oxidative stress tau protein hyperphosphorylation etc At present acetylcholinesterase AChE inhibitors NmethylDaspartate NMDA receptor antagonists or a combination of them are used clinically to increase the content of neurotransmitters in the synaptic space to alleviate cognitive and behavioral disorders

[30095897]

the exposition of ad transgenic mouse models to a high fat andor high sugar diet exacerbates the ad pathology

[27863851 29427755 22427376 21762376 27177549]

The connection between T2DM and AD has been studied using different approaches, extensively described in Section 4 of the present review. for instance postmortem brains of ad patients present a deregulation of the insulin receptor ir intracellular signalling

[14769913 15750215 15773910]

since 2020 numerous studies have described various effects that sarscov2 has upon the brain with recent data showing reduced grey matter thickness and increased cognitive decline in people over the age of 51 with infection

[32637987 33399270 33836148 33257876 33031735]

in relation to broader health implications our findings may have some relevance and thus warrant some brief reflections in relation to the recent emergence of ace2 as the primary receptor for severe acute respiratory syndrome coronavirus 2 sarscov2 that has caused a global health pandemic since 2020 infection with sarscov2 has been shown to downregulate membraneexpressed ace2 potentially leading to overactivation of cras and elevated production of angii mediated vasoconstriction and inflammation underpinning pathological processes associated with sarscov2 infection and covid19 disease

[]

these brain changes include increased atrophy brain aβamyloid and tau pathology hallmarks of ad as well as reduced brain glucose metabolism

[25186857 25061245 27091528 31209175 24107601]

the presence of sleepwake disturbances in dementia due to ad is wellestablished crucially rather than presenting only as a comorbidity mounting evidence indicates that sleep disturbances increase risk of cognitive decline and dementia by modulating neurobiological brain changes

[14998915 22467987 23905991]

the positive effect observed in the souvenaid group alone coincides with the findings presented by other studies showing the efficacy of souvenaid in improving cognitive function in people with mci and mild ad while maintaining a good safety profile

[20129316 22766770 29097166 32920957 31259306]

regarding treatment with souvenaid alone, a significant improvement over achei alone was seen in svft, pvft, and npi after the 12-month follow-up. in addition, the souvenaid group also showed an improvement already at 6 months in svft and npi.

[]

consistent with links between the blue module and cancer we find that many blue module hub genes such as moesin msn yap1 tead1 and wwtr1 are well known for their role in cancer and mediate the emt module eigengenes defined as the first principal component of a module can be used to measure the degree of similarity between modules in a network based on principal component analysis pca we find a negative association between eigengenes of the blue cancerrelated module versus eigengenes of the turquoise neurotransmission module e

[28581497 19952108 22190458 19432821 18031580]

“hub genes” are defined as the most highly connected genes within a module. we identified hub genes of each module by ranking genes according to their intramodular connectivity kin and selecting the top 15 of the most highly connected genes d

[]

s1b of genes that change significantly in braak vvi samples fig 1b and identified three main myeloid clusters homeostatic microglia hmg p2ry12 cx3cr1 activated microglia amg pu1 csf1 cd45 cd74 15 24 35 50 and a third group including nonclassic microglial markers which we termed cd163 cluster cd163 ifitm3 ccr2 cd68 and msr1

[29346778 28602351 29403371 29310663 30559476]

significance, indicated in the figure, was tested using the kruskal–wallis test followed by the dunn test Next, we performed a hierarchical cluster analysis (Additional file 1: Fig.

[]

at2r and masr activation decrease inducible nitric oxide synthase inos and the levels of inflammatory cytokines such as cxc motif chemokine ligand 12 cxcl12 interleukin 1β il1β and il6 produced by m1 microglia while increasing antiinflammatory markers such as il10 and il4

[24487585 27761230 23583926 28192099 26448556]

the upregulation of at1r in m1 microglia is associated with inflammation and cognitive impairment through a tolllike receptor 4 tlr4dependent mechanism 142 thus the at1rmediated activation of proinflammatory m1 microglia exacerbates inflammation eventually causing ad moreover, the activation of at2r shifts microglia toward an m2 phenotype.

[26637556 24487585]

nk killer cells leukocytes 117118119 and lymphocytes including human peripheral blood lymphocytes also contain α1ars but the subtypes are not clearly defined

[18463421 35537053 9119969 10024333 11350496]

human neutrophils contain the mrna for all three α1ar subtypes monocytes contain the mrna for the α1band α1dars

[25561369 21771488]

a dependence on polymorphisms in both the bdnf gene and related receptors which may increase the risk of developing neuropsychiatric disorders has been described in numerous studies

[22047184 18852698 29102837 21936709 35099506]

these relationships were described in the work of porcher et al., which showed that bdnf may have a differential effect on gabaergic synaptic inhibition depending on factors such as: the stage of neuronal development, the function of a particular area of the brain, or the rate of the delivery of exogenous bdnf. the authors of the study believe that the seemingly opposite effect of bdnf in this regard may contribute to the maintenance of the homeostasis of gabaergic transmission

[30210299]

pivotal roles of macrophages at brain surfaces and their significance in brain homeostasis are highlighted in recent literature

[21952260 31358892 36352225 35794106 19164591]

furthermore, this brain drainage system links the health of cerebral vasculature with brain inflammation, stressing critical inter-relationships between brain blood vessels and neuroimmunity. given these recent neuroscientific advances and knowledge on lymphatic diseases in peripheral tissues, a vascular–immune basis for ad is conceivable and evidence in support of specific pathways and mechanisms of brain fluid and metabolite clearance is now emerging rapidly across species.

[]

moreover a handful of biomarkers have also been incorporated into the clinical diagnostic process including structural neuroimaging eg magnetic resonance imaging mribased measures of hippocampal volumes 11 12 blood and urine samples 13 cerebral spinal fluids eg tau and betaamyloid levels 14 and genetic risk profiling

[12595205 20139996 22078169 20538373 26312828]

As such improving early diagnostics has become a fundamental element in AD research and therapy 5 especially since there are currently no cures for AD while a definite diagnosis for ad can only be achieved through a postmortem structural examination of the brain clinical diagnosis currently relies on the use medical history and exams such as the minimental state examination mmse 9 and the clinical dementia rating cdr

[18579155]

in addition the correlation between blood nfl and aβ deposition was not identified

[31514172 28346578 31572170 32211500 30055655]

by comparison it is relatively clear that its levels increased faster in patients with preclinical ad specifically trajectory analyses revealed that mean plasma nfl levels increased 34 times faster in participants who developed ad versus those who remained healthy and that these changes were detectable 96 years before diagnosis

[32206776 31009028 31673598 32206776]

comparatively its levels are more likely to reflect csf ttau concentration cognitive level brain atrophy rate metabolic function and white matter alterations

[31514172 31572170 29070659 31009028 32211500]

specifically trajectory analyses revealed that mean plasma nfl levels increased 34 times faster in participants who developed ad versus those who remained healthy and that these changes were detectable 96 years before diagnosis in addition the correlation between blood nfl and aβ deposition was not identified

[32206776 31514172 28346578 31572170 32211500 30055655]

this dysregulated erca2 signaling disrupted synaptic transmission and plasticity propagated inflammatory responses and drove pathogenic amyloid and tau formation all of which was normalized with ryanodex treatment in the ad models

[19641109 23284867 10764737 20826675 32033164]

bafilomycin (25nm; 4h) did not significantly alter ryr-evoked ca2+ release in either 3xtg-ad (28.47%±16.54% over baseline) or ntg (8.62% ± 2.99% over baseline) neurons, again showing minimized interference of bafilomycin to ryr-evoked ca2+ release. these results are consistent with previous studies that demonstrated altered upstream er-ca2+ homeostasis in multiple ad mouse and human neuronal models.

[]

these proteins include 1 singletype proteins such as aβ40 aβ42 aβ oligomers aβo total tau ttau tau phosphorylated at threonine 181 ptau 181 tau phosphorylated at threonine 217 ptau 217 or tau phosphorylated at threonine 231 ptau 231 and 2 combined types such as the aβ42aβ40 ratio the ratio of amyloid precursor protein669771 app669771 to aβ42 aβ42app669771 ratio the aβ42aβ43 ratio the ttauaβ42 ratio or the ptau 181aβ42 ratio

[32806668 32899797 35175385 33910450 35453600]

ad predicted to affect more than 152 million people by 2050 is now recognized as common senile dementia with main pathological hallmarks such as extracellular neuritic plaques containing amyloidβ peptide aβ and intracellular neurofibrillary tangles composed of hyper phosphorylated tau some proteins related to the two biomarkers detected in the peripheral blood are attractive candidates for ad diagnosis 89101112 because they are contained in the amyloid cascade hypothesis which introduces the idea that aβ misfolding and deposition are the primary precipitants of ad

[21456963 32806668 32899797 35175385 33910450 35453600 35573283]

previous studies have shown that reactive astrocytes can precede early pathological hallmarks of ad such as aβ and tau during disease progression

[22213821 30611668 25893384 26813969 26553227]

in pathological situations astrocytes undergo a series of morphological and functional alterations collectively referred to as reactive astrocytes and overexpress proteins such as gfap reactive astrocytes contribute to neuroinflammatory changes in ad by releasing cytokines inflammatory mediators nitric oxide and reactive oxygen species and promoting redox status imbalance

[17090684 19944719]

in circulation nearly all igfs are bound to igfbps with only 013 of total igf2 being free to bind receptors the halflife of free igf2 in circulation is 10 min while the halflife is 30 min for the igf2igfbp binary complex and 12 h for a ternary complex that also contains the protein acidlabile subunit als however only the binary complexes are able to cross from capillaries into tissue free igfs can diffuse across capillary pores to act directly within tissue although the physiological significance of these free igfs is not known in addition to producing igfs locally tissues can dynamically regulate the action of circulating igfs by secreting enzymes capable of degrading igfbps thereby liberating the igfs within binary complexes

[18719053 7514998 7523391 15964556 20826314]

additionally, igf1 and igf2 bind six high‐affinity igf‐binding proteins (igfbps), which regulate the action of igfs by sequestering them away from receptors. igfbps generally inhibit the action of igfs, but may in some cases enhance their biological action by protecting them from degradation.

[]

a striking manifestation of neurotrophic decline in ad is the reduction in hippocampal neurogenesis that occurs across disease progression in neurologically healthy subjects hippocampal neurogenesis declines with age but this decline is more dramatic in ad subjects rodent studies have indicated a role of hippocampal neurogenesis in many neurological processes that are impaired in related to ad including memory consolidation and neuroprotection

[30911133 30911133 29625071 14614143 20204139 12440573]

the synaptic compartment is likely to be an early site of igf2 dysregulation in ad. in a rat model of agerelated cognitive decline reduced igf2 expression in the synaptic compartment was associated with cognitive deficits even as overall igf2 expression showed no apparent decline since total igf2 expression eventually declines dysregulation of synaptic igf2 may represent an early event in the typical progression of ad

[27318130]

because protooncogenic cells often upregulate igf2 in order to evade apoptosis it is plausible that exogenous igf2 might increase the risk of a precancerous tissue surviving to become tumorous in transgenic mice that overexpress igf2 in specific tissues tumor formation tends to increase in those tissues where igf2 is overexpressed however such models do not give a clear indication of how systemic administration of exogenous igf2 would influence cancer risk as most tissues also secrete igf2 for use in paracrine and autocrine signaling

[18087038 27140600 7577466 12584565 9571768]

the hypoglycemia risk of intranasally administered igf2 is likely to be even lower since a negligible amount of the intranasally administered compound enters general circulation whereas 40 iu subcutaneous insulin would provoke hypoglycemia in humans this same dose of intranasal insulin was not associated with acute or chronic hypoglycemia because igf2 is less effective than insulin in stimulating glucose uptake even a large dose of intranasal igf2 would be unlikely to cause hypoglycemia another potential risk of therapeutic igf2 is increased cancer incidence.

[32568367]

sfdi is a relatively new technology designed to quantitatively map tissue absorption and scattering over a wide fov to perform this measurement a typical hardware setup for sfdi includes a camera sensor a light source with one or more wavelengths a digital micromirror device dmd and a computer for triggering acquisition and processing sfdi uses a dmd to project spatially modulated patterns either from a broadband source or multiple discrete wavelengths onto the tissue and detects the backscattered light with a camera

[15981531 19405742 23764696 29296630 33842666]

despite some of the limitations associated with traditional lsi, it has been extensively used in diseased and healthy rodent brains. in this review, we highlight areas that lsi has been applied.

[]

however interpreting these observational associations as evidence of causal relationships between education brain structure and alzheimers risk relies on several untestable and potentially implausible assumptions including the absence of residual andor unmeasured confounding and reverse causation for instance the association of education with brain structural metrics may be confounded by earlylife factors that are common predictors of both ea and brain structure such as childhood socioeconomic status birthweight childhood cognitive ability and maternal smoking during pregnancy confounding may also affect the relationship between mri markers of structural brain reserve and alzheimers risk

[25064373 22880000 25821911 27664981 22180574]

for instance higher education levels have been associated with increased wholebrain and regional grey matter volume cortical thickness and increased surface areas of subregions of the hippocampus and amygdala that are vulnerable to alzheimers disease pathology similar findings have been reported for the association between education levels and white matter microstructure in cognitively intact elderly with more highly educated individuals showing increased white matter tract integrity in several brain regions that are characteristic sites of alzheimers pathology given the observed associations between education and structural markers of brain reserve, it is plausible to hypothesize that changes in brain structure may mediate the protective effect of education on alzheimer’s disease risk, through determining the underlying brain reserve of the individual.

[23796547 27535872 27535407 21853422 19433891]

previous reports established that by inhibiting the essential proteins such as cholinesterase monoamine oxidases rock2 calcium homeostasis modulator1 calmh1 glycogen synthase kinase3 beta gsk3β nmethyldaspartate nmda receptor and betasite app cleaving enzyme 1 bace1 or bace can lessen the memory loss and neuronal death

[34944045 34577637 35745697 35741655 36122738]

furthermore the deposition of amyloid plaques and oxidative stress can result in the hyperactivation of gsk3β which increases the phosphorylation of tau proteins and potentiate the formation of neurofibrillary tangles moreover the hyperactivation of nmdareceptor nmda in combination with neurofibrillary tangles and amyloid plaques raises the release of glutamate which could lead to excitotoxicity and neuronal death

[34776454 30800052]

working memory semantic knowledge attention motor performance and visuospatial ability are among the functions included in the task mode the posterior cingulate cortex entorhinal cortex and hippocampus were evaluated in this mode but the most engaged structure was medial temporal lobe nonetheless fmri is not used in routine clinical evaluation possibly because of its low snr for neuronal activity

[16402259 23497150 10211471 12486265 9106749]

the cbf is reduced significantly in ad individuals in temporal frontal parietal thalamus hippocampus and amygdala furthermore lower cbf has been shown to be associated with faster cognitive decline in ad individuals although this modality is noninvasive and nonionizing alterations in signal intensity and the low signaltonoise ratio snr reduce image quality fmri is a bloodoxygenleveldependent or boldcontrast imaging technique individuals can be evaluated for brain activity during the task or resting state studies showed that hippocampal and medial temporal lobe have low activation rates in ad individuals

[21786091 24670395 27334014 29853806 19588145 11449264 22333920]

overall jedited fmrs has high sensitivity and specificity for taskinduced lactate modulation and shows the rate of increase in lactate concentration compared with the fixation condition a significant increase was detected in lactate levels the rate of lactate increases significantly between 7 and 15 percent in addition the result shows that lactate increased on activating the visual cortex but did not change on deactivating the posterior cingulate cortex however increases in lactate during motor stimulation are less significant figure figure

[30201463 24555953 30201463 33472521 31995265 20404151 33472521 24555953]

the megapress is a jdifference edited mrs pulse sequence consisting of on and off subexperiments in contrast to the off experiment the on experiment uses frequencyselective radio frequency editing pulses to edit the lactate molecules 132 ppm resonance lactate is separated from overlapping resonances and macromolecules using spectral editing with jmodulation which uses the quantum mechanical characteristics of specific molecules to edit them out of the overall 1hmrs spectrum on the other hand jediting is prone to subtraction mistakes caused by motion which can hide tiny changes in the lactate by using quantum mechanical characteristics of lactate to remove it from the overall spectrum jedited 1hmrs can provide direct insights into the overlapped resonances that occur from numerous molecules such as fatty acids or macromolecules because of considerable suppression of the relatively short t2 for the lipid and macromolecule background signals 1hmrs has demonstrated that physiological modulations of lactate in the visual cortex may be seen even at 15 t using long te

[12815674 30201463 30201463 33472521 31995265]

as well as deteriorating cognitive functions 5 47 62 patients with ad show circadian dysfunctions even at preclinical stages that may contribute to disease severity

[21371747 27188934 26921134 29379963 17383938]

disturbed circadian rhythm and retinal degeneration in a mouse model of alzheimer’s disease alzheimers disease ad the most prevalent form of dementia worldwide is characterized by aggregation and accumulation of amyloidβ aβ and hyperphosphorylated tau protein in the patients brains

[]

amyloidβ and tau bind iron through histidine and possibly other residues

[20164601 21800824 30174587 12358761 30250423]

among the profile of altered enzymes in ad a decreased activity of pitrm1 could contribute to the formation of amyloid and tau deposits in ad since both amyloidβ and tau bind iron they are likely participants in the sequestration of iron in patients with ad

[32632204 21750375 24561226 34356897 26697887 9237552 10617129 31927402 30174587 33532700]

in fact some studies show that the practice of mbi favoring the controlled attention component and therefore the cognitive control of active memory working memory at the present moment without judging the emotional or thought contents could help reduce these adverse factors 27282930 reducing response interference

[28323668 33010903 29466242 23115195 26639952]

in fact, mbis constitute primary prevention interventions for health in general and can be used as secondary prevention in the field of physical and mental health, even in neurodegenerative diseases such as ad. Furthermore stress depression anxiety and neuroticism affect sleep cognition and mental health and wellbeing in aging populations and are associated with an increased risk of AD and further degeneration

[]

genes in green font were prioritized or nominated through integration analyses thus human genetics evidence strongly suggests that efferocytosis may act as a pathogenetic hub for alzheimers disease in macrophages including microglia in the brain

[33589840 35379992 33712570 35931864 34992268]

adaptation, storage, elimination). with the exception of genes colored in gray, all genes shown in this figure to be involved in the various steps of efferocytosis have also been implicated in the etiology of ad by gwas and post-gwas studies.

[]

genes in green font were prioritized or nominated through integration analyses thus human genetics evidence strongly suggests that efferocytosis may act as a pathogenetic hub for alzheimers disease in macrophages including microglia in the brain

[33589840 35379992 33712570 35931864 34992268]

adaptation, storage, elimination). with the exception of genes colored in gray, all genes shown in this figure to be involved in the various steps of efferocytosis have also been implicated in the etiology of ad by gwas and post-gwas studies.

[]

in neuropathology studies similar positive associations were recorded against various aβ staining methods such as thal cerad and thioflavin stain scores

[33585983 34725927 32722745 32720099 35195758]

More recently a comparative study that evaluated ptau181 ptau231 and ptau217 in a headtohead manner demonstrated that ptau217 quantified by IPMS technology discriminated with higher accuracy patients with MCI and those who progressed to AD dementia plasma ptau levels significantly associated with csf aβ42aβ40 as well as with aβpet accumulation in early accumulating brain regions eg precuneus temporal and superiorfrontal areas in preclinical stages which became stronger and extended to lateaccumulating regions eg subcortical structures later in the disease course

[33106600 33169916 33585983 32720099 32123385 33479777]

for example ad and especially adrd is often underreported on death certificates this problem affects the black and hispanic population more than nonhispanic white population the impact of this problem increases with age and is exacerbated by higher misreports of an individuals exact age in these higher age brackets finally many studies on racial differences in adadrd risk use oversimplified models that cannot account for the complex interactions between risk and protective factors determining what is observed in the data

[10404929 24583403 32852519 29094262 35678407]

for example studies have suggested that some of the raceethnicityrelated disparities in adadrd could be caused by healthier individuals within a group who survive past the initial ages of higher mortality risk to older age thus surpassing the average life expectancy of the group this could lead to the effects such as the hispanic paradox which refers to the comparableorbetter survival in hispanic american groups despite their lowerthanaverage socioeconomic status and education level the healthy migrant successful migrants have better initial levels of health and salmon agingsick migrants moving back to their home country effects operate through a similar mechanism differences in health especially agerelated comorbidities and adadrd risk factors play an important role in survival and attrition and when these are ignored can lead to misleading findings mismatched linkages and overall quality of mortality data can also present a problem.

[22698043 510638 15074127 23644828]

partial aggregated and oligomerized intracellular aβ was documented to be cytotoxic and synaptotoxic in cell culture and in vivo

[11182300 11207825 12834113 10623648 15304237]

regarding the interaction with iron it was found that fe3 influences the formation of amyloid fibrils of aβ142 56 and aβ2535 the interaction of redoxactive fe3 with aβ fibrils results in their chemical reduction and concomitant generation of reactive oxygen species ros causing lipid membrane peroxidation dna breakdown and protein oxidation

[15201484 11833745 12689772 14499458 15053949 15231239]

adad shares the neuropathological hallmarks of alzheimers disease ie neuritic plaques and neurofibrillary tangles composed of amyloidbeta aβ peptides and hyperphosphorylated tau respectively the order of adad pathologies as measured by biomarker abnormalities in presymptomatic and symptomatic phases of the disease continuum are reported to largely conform to those in sporadic alzheimers disease and also align to the atn aβ tau and neurodegeneration classification these similarities and the deterministic and predictable onset of symptoms in adad mutation carriers mc have made adad an important model for sporadic alzheimers disease in general

[21211070 22784036 30217935 29653606 27371494]

plasma biomarker profiles in autosomal dominant alzheimer’s disease autosomal dominant alzheimer's disease (adad) is caused by pathogenic mutations in the amyloid precursor protein (app), presenilin 1 (psen1) or presenilin 2 (psen2) genes.

[]

platelets are one of the major sources of blood circulating amyloid beta 21 22 and plateletderived amyloid beta seems to be involved in the formation of cerebrovascular 24 26 and cerebral amyloid beta deposits

[32681097 7639768 27221710 30341392 33668038]

Females in both experimental groups showed weight loss (Supplementary Table 2), whereas only platelet-depleted males lost weight during the experiment. the efficiency of platelet depletion in the brain was similar between females and males, with platelet-depleted mice showing about 97% lower platelet numbers in the brain compared with sex-matched igg treated mice (hippocampus: females: igg = 920.3 ± 528.9 platelets/mm3 versus αcd42b = 26.6 ± 10.88 platelets/mm3; males: igg = 563.4 ± 473.8 platelets/mm3 versus αcd42b = 16.67 ± 5.51 platelets/mm3).

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several papers in this field contain uncorroborated behavior endpoints such as acoustic startle prepulse inhibition psychomotor vigilance object in place recognition operant responding and conditioned taste aversion that like our strengthendurance measures would need repetition before meaningful interpretation

[15803624 24611657 24949841 22468701 12793763]

other behavior endpoints: our study adds wire hang and grip strength tests to the literature. here we observed small changes of uncertain biological significance in wildtype mice but not transgenic mice.

[]

the presented molecular mechanism can be used for building correlations between different enzymebased cellbased animal and clinical studies of alzheimers disease

[21320126 26051801 23308095 22479317 33662398]

the second substrate binds to the most dynamic sites in γ-secretase’s structure that can be affected by disease-causing fad mutations and by different drugs. the presented two-substrate mechanism can explain many of the pathogenic changes in γ-secretase activity at the molecular structural level.

[]

the presented twosubstrate mechanism is the first mechanism that can explain the apparently conflicting observations that both the c99βctfapp substrate and different aβ products can lead to pathogenic events

[18234110 22537414 30071370 23152608 29867356]

Toxic aggregation between the N-terminal domains of the two substrates can be controlled by the closure of the nicastrin ectodomain (Figure 3, Figure 4, Figure 5 and Figure 6). Closure and opening of the nicastrin ectodomain can be controlled by supramolecular interaction between β-secretase and γ-secretase (Figure 8A).

[]

astrocytes are the most abundant glial cells in the brain and play a vital role in maintaining brain homeostasis when ad occurs the deposition of aβ will induce astrocytes to transform from a resting state to a reactive state which is manifested by increased levels of glial fibrillary acidic protein gfap which in turn produce more proinflammatory cytokines and mediators such as interleukin1β il1β tumor necrosis factorα tnfα and interleukin 6 il6 which exacerbates the progression of inflammation additionally recent data found a specific accumulation of astrocytes associated with proinflammatory diseases in ad therefore inhibiting astrocytemediated inflammation may be a potentially effective strategy for reducing cognitive impairment in ad patients

[27443914 23595014 32507685 22727944 32341542]

ave 0991 suppresses astrocyte-mediated neuroinflammation of alzheimer’s disease by enhancing autophagy alzheimers disease ad is a progressive neurodegenerative disease characterized by impairments in learning memory and cognition as well as changes in mood previously mainstream research focused on the pathogenic effects of the two main ad drivers aβ peptide aβ and hyperphosphorylated tau hptau protein recently more and more evidence indicated that neuroinflammation plays a central role in the pathogenesis of ad emerging studies have suggested that controlling neuroinflammation mediated by glial cell activation is an important therapeutic strategy for ad and previous reports have also found that the glial responses activated by aβ can promote the release of proinflammatory cytokines to cause neuronal dysfunction and memory impairment therefore targeting neuroinflammation induced by glial activation may be an effective way to slow or prevent the progression of ad

[]

since the average age of the control group at the end of the study was around 86 years it is expected that between 20 and 40 of the 25 control cases should be presymptomatic for different neurodegenerative diseases

[35697880 35099509 25988462 31961372 29508259]

by analyzing the data using biomarker panels tailored for these sex differences, a significantly higher percentage of ad cases (96%—all but one male ad case) were identified, where most of these cases could be diagnosed using the earliest available plasma samples (16 out of 25), including 15 out of 24 cases diagnosed pre-symptomatically. Quite notably, diagnosis of AD using the sex-biased biomarker panels detected a higher percentage of AD cases (96% vs. 88%) at an earlier time point (6.3 vs. 6.0 years before clinical AD diagnosis) (Table 4).

[]

reduced levels of the hormone have consequently been associated with aβ accumulation tau hyperphosphorylation oxidative stress and neuron loss which contribute to ad progression

[25045655 35021306 26154489 30632505 31746286]

the hormone exerts protective effects on neuronal synapses by preserving the production of presynaptic proteins including synaptophysin synaptotagmin and synapsin1 7475 and has thus been reported to contribute towards the maintenance of dendritic spine density synaptic integrity and synaptic plasticity in the hippocampus which underlie learning and memory propensity depletion of testosterone in the hippocampus has been shown to induce oxidative stress and neuronal damage leading to a reduction in antioxidants upregulated expression of caspase3 and subsequent neuronal apoptosis

[25045655 31805308 17132744 27599230 35021306 33691594]

the concept that ad and glaucoma may share a common underlying vascular aetiology has been increasingly investigated over recent years and evidence of vascular dysfunction that was related to either disturbed vascular autoregulation or disturbed neurovascular coupling mechanisms has been previously demonstrated at the cerebral 383940 and ocular level in both conditions but separately

[15140605 16540327 21205781 26498862 29119370]

indeed, the time taken for the retinal arteries to reach the point of maximum dilation following the onset of flicker light stimulation was found to be significantly greater in both ad and poag patients in comparison to healthy controls, on the final flicker cycle. furthermore, the sequential changes in the rt of the retinal arteries on progressing from flicker 1 to flicker 3 was found to vary significantly between all study groups with healthy controls showing a significant faster rts on heading into the final flicker cycle, which was not replicated by any of the diseased groups.

[]

an in vitro study reported that mesenchymal stem cells mscs from c57b6 mice exposed to pbm therapy presented an increased phagocytic state toward aβ whereas yang et al observed a pbmdriven normalization of inflammatory responses through the downregulation of proinflammatory factors in primary astrocytes exposed to aβ accordingly pbm animal studies have detected a decrease in proinflammatory markers in ad transgenic and nontransgenic models such as interleukin 1β il1β tumor necrosis factor α tnfα and transforming growth factor β tgfβ with some studies also demonstrating reduction of hyperactivated glial cells accompanied by decreased aβ andor tau load

[24994540 20884337 21116053 27815990 28255783]

moreover two vs protocols led to a significant decrease of levels of hyperphosphorylated tau assessed by different tau phosphoepitopes in the visual cortex of p301stau mice hence despite the preclinical evidence reporting the beneficial effect of pbm and vs on tau pathology no pbm or vs clinical study has monitored tau pathology in the human brain among the 43 included articles, 12 of them reported alterations in immunological activity induced by light stimulation.

[27929004 31076275]

vr technology has also been reported to be used for people with mild cognitive impairment mci people at high risk of cognitive decline memory rehabilitation patients with noncommunicable diseases ncds patients with ncds due to traumatic brain injury stroke patients and patients with severe ncds due to ad

[33101098 24998488 26158918 26029101 29507261]

additionally people also want to know what they can do to delay the onset or reduce their risk of developing ad virtual reality vr technology has been widely used in rehabilitating older adults with medical conditions to enhance their ability to perform activities of daily living in the last years

[34354619 31547137 34318524]

many studies 625 met the criteria for moderate immersion with the remainder being 125 high immersion 125 low immersion experiences and 125 information unavailable for immersion

[22261206 30409202 28655135 31409559 32349413]

virtual reality (vr) levels of immersion, characteristics of the vr programs, and user experience. shows the objective level of immersion based on the five criteria developed by slater et al

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in addition neuroinflammation caused by glial cell activation plays an essential role in ad

[25792098 27179961 26984188 30349474 33318676]

however, how toxic conformers contribute to the progression of ad pathology has not been studied in detail. this study investigated age-dependent phenotypic changes related to ad pathology in nl-p-f mice.

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it should be noted that oxidative stress alters lipidlipid interaction leading to impaired membrane permeability 76 and high levels of markers of oxidative stressinduced lipid peroxidation and cytotoxicity such as 4hydroxynonenal mda or thiobarbituric acid reactive substances are increased in ad 77 78 and diabetes supporting a synergistic effect when both diseases coexist

[28212725 28098243 35227014 35245527 24999379]

likewise advanced glycation end products resulting from hyperglycemia in t2d alter the structure and function of bbb proteins 62 and diabetesinduced inflammation leads to astrocytic feet swelling in small vessels separation of the plasma membrane and accumulation of hypertrophic microglia our in vivo observations were also confirmed by postmortem assessment of oxidative stress and an overall increase of lipid peroxidation was observed in ad-t2d animals, when compared with ad alone.

[30618559 35299293]

recent studies have suggested that bbb dysfunction is correlated with human cognitive impairment 239 including the early clinical stages of ad and is considered as an early biomarker of the disease

[30643288 29377008 25611508 27243267 27459939]

vascular dysfunction in ad accelerates bbb breakdown 237242 degeneration of pericytes 237 240 243 244 and reduction of bbbassociated cells that maintain integrity the presence of vascular aβ pathology also called cerebral amyloid angiopathy caa predisposes toward neurovascular impairment and sometimes stroke

[23126372 22857991 30340601 30643288 22857991 33567873]

during obesity the expanded adipose tissue secretes proinflammatory factors and the ffas which reach the bloodstream and lead to tonic activation of the innate immune system and to maladaptive responses such as fibrosis necrosis and altered secretion of local proinflammatory factors which cause significant tissue damage in multiple organs including pancreas liver skeletal muscle heart and brain

[15677759 24593134 20035279 17578888 21633177]

in the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in t2d and ad, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives. lowgrade chronic systemic inflammation is an established hallmark of lipotoxicity

[14679176 25729921 28045402]

interestingly as opposed to microglial large evs neuronal and neuroblastoma cell line small evs seem to promote amyloidogenesis of soluble aβ through the binding of the amyloid peptide to the glycosphingolipid glycans 616292 and to the cellular prion protein prpc present on their surface

[22303002 25037226 25741766 19242475 26710111]

indeed the amyloid precursor protein app and its metabolites including the aβ peptide have been shown to be secreted within neuronderived small evs in addition sardar sinha and colleagues demonstrated that the impairment of the formationsecretion of small evs can suppress the diffusion of aβ oligomers to other neurons

[16837572 18171695 17468104 19773092 28956068 29934873]

glp agonists such as liraglutide and exendin4 have been shown to increase insulin sensitivity in the periphery 979899100 and the brain

[30371206 31034184 32139381 28572610 29435980]

more recently a phase iii clinical trial to assess the efficacy of pioglitazone in protecting against progression to mci was terminated when a futility analysis revealed that there was no likely benefit in preventing a cognitive decline more recent interest has been in evaluating glucagonlike receptor glp agonists as these agents offer the advantage of crossing the bbb and exerting direct neuroprotective effects

[34146512 29412810]