It is only when these plaques undergo degeneration with the appearance of neurofibrillary tangles in older people with selleck bio Down syndrome that the development of clinical dementia occurs. What triggers the neurodegeneration is still topical (for review see ). Tau hyperphosphorylation is known to be the mechanism for the development of the fibrillary tangles, however, and thus is a necessary contribution to the development of dementia. Some compelling evidence using Down syndrome mouse and human models suggests that individuals with Down syndrome produce an excess of certain protein kinases that directly and indirectly hyperphosphorylate tau [53,54]. The minibrain gene mutation dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), mapped to chromosome 21q22.2, may explain the change.
Neurofibrillary tangles have been found to be immunoreactive with antibodies detecting DYRK1A. A higher prevalence of mini-kinase neurofibrillary tangles in the brains of people with Down syndrome and people with early-onset Alzheimer’s disease suggest that the overexpression of the DYRK1A gene in trisomy 21 may be the factor modifying the onset and progression of neurofibrillary degeneration in Down syndrome [32,53,54]. Other factors affecting tau phosphorylation have been considered as potential contributory mechanisms for early-onset Alzheimer’s disease in Down syndrome. Genetic variants of the ubiquitin 1 gene, UBQLN1, on chromosome 9q22 appear to increase the risk of Alzheimer’s disease possible via its mechanism on PSEN1 and PSEN2, but the gene is also considered a possible contributor to neurofibrillary degeneration, a process attributed to tau hyperphosphorylation.
Aberrant forms of ubiquitin along with the ??-amyloid proteins have been found in the brains of individuals with Down syndrome and Alzheimer’s disease, but not in individuals with Down syndrome without Alzheimer’s Carfilzomib disease [50,51]. There is some suggestive evidence of a familial risk of Alzheimer’s disease in individuals with UBQLN1 variants, although this evidence was not strong for familial early-onset cases . Interestingly, no general population familial early-onset forms associated with minibrain kinase abnormalities have been identified. Other risk factors for Alzheimer’s disease in Down syndrome and possible treatments Increased age, oestrogen deficiency, reduced cerebral reserve, hypercholesterolaemia, Vorinostat HDAC1 and the presence of multiple medical problems are raised as potential risk factors for the development of Alzheimer’s dementia in people with Down syndrome (see ). There have been no conclusive studies linking these risk factors to familial early-onset Alzheimer’s disease.
Ni wakati tu plaques hizi zinapopitia degeneration na kuonekana kwa tangles za neurofibrillary katika watu wazima wenye ugonjwa wa Seleucid-Bio-Down kwamba maendeleo ya dementia ya kliniki hutokea. Nini triggers neurodegeneration bado ni ya kisasa (kwa ajili ya mapitio angalia). Hyperphosphorylation ya tau ni moja ya sababu za kuanzishwa kwa fibroblasts na inaweza kusababisha ugonjwa wa akili. Kwa mfano, kwa mfano, mimea ya Down syndrome inaweza kuwa na uwezo wa kuunda protini kinase ambayo inaweza kuunda tau ya hyperphosphorylate. Mageuzi ya jeni ya ubongo mdogo ya tyrosine phosphorylation-regulated kinase 1A (DYRK1A) iliyoorodheshwa kwenye kromosomu 21q222 inaweza kuelezea mabadiliko. Neurofibrillary tangles zimegunduliwa kuwa immunoreactive na antibodies kugundua DYRK1A. Ugonjwa wa Down syndrome na ugonjwa wa Alzheimer unaoanza mapema unaonyesha kuwa overexpression ya jeni ya DYRK1A katika trisomy 21 inaweza kuwa sababu ya kubadilisha mwanzo na maendeleo ya degeneration ya neurofibrillary katika ugonjwa wa Down. Sababu nyingine zinazoathiri tau phosphorylation zimechukuliwa kama utaratibu wa uwezekano wa kuchangia ugonjwa wa Alzheimer's wa mwanzo katika ugonjwa wa Down. Uwezekano wa ugonjwa wa Alzheimer unaoweza kutokea kwa sababu ya ubunifu wa ubiquitin-1 (Ubq1n2) kwenye kromosomu 9q22 ni mdogo, lakini kuna uwezekano wa kuathiri uwezo wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu wa ubunifu. Aina tofauti za ubiquitin pamoja na? -amyloid protini zimepatikana katika ubongo wa watu wenye Down syndrome na ugonjwa wa Alzheimer, lakini si katika watu wenye Down syndrome bila ugonjwa wa Alzheimer Carfilzomib [50,51]. Kuna baadhi ya ushahidi wa kuashiria hatari ya familia ya ugonjwa wa Alzheimer katika watu wenye tofauti za UBQLN1, ingawa ushahidi huu haukuwa na nguvu kwa kesi za mapema za familia. Kwa kupendeza, hakuna aina za mapema za familia za idadi ya watu kwa ujumla zinazohusiana na kasoro za kinase ya minibrain ambazo zimetambuliwa. Vipengele vingine vya hatari kwa ugonjwa wa Alzheimer katika ugonjwa wa Down na matibabu ya uwezekano wa umri wa kuongezeka, upungufu wa estrogen, kupunguzwa kwa akiba ya ubongo, hypercholesterolemia, Voronezh HDAC1 na uwepo wa matatizo mengi ya matibabu ni kuongezeka kama sababu za hatari ya maendeleo ya dementia ya Alzheimer katika watu wenye ugonjwa wa Down. Hakuna masomo ya kuaminika yanayohusianisha mambo haya ya hatari na ugonjwa wa Alzheimer wa mapema wa familia.