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Alzheimer disease (AD) is the most common cause of age-related dementia, affecting more than 25 million people worldwide. The accumulation of insoluble β-amyloid (Aβ) plaques in the brain has long been considered central to the pathogenesis of AD. However, recent evidence suggests that soluble oligomeric assemblies of Aβ may be of greater importance. β-Amyloid oligomers have been found to be potent synaptotoxins, but the mechanism by which they exert their action has remained elusive. Herein, we review the recently published finding that cellular prion protein (PrPc) is a high-affinity receptor for Aβ oligomers, mediating their toxic effects on synaptic plasticity. We further discuss the relationship between AD and PrPc and the potential clinical implications. Cellular prion protein may provide a novel target for therapeutic intervention in AD.
Alzheimer disease (AD) is a debilitating neurodegenerative disorder, estimated to affect at least 26.6 million people worldwide.1 Over the next 40 years, this number is predicted to increase 4-fold,1 stressing the need for more effective therapeutics. For many years, the leading hypothesis for the pathogenesis of AD has involved the toxic effects of a gradual buildup of β-amyloid (Aβ) plaques in the brain.2 β-Amyloid is produced after sequential processing of the amyloid precursor protein (APP),2 and increased levels of the Aβ1-42 species are thought to be a key early event in AD.3 A major criticism of the amyloid hypothesis has been that the burden of fibrillar Aβ, the insoluble species constituting plaques, correlates poorly with the degree of dementia4 and brain atrophy,5 and cognitively normal individuals may have significant plaque deposition at autopsy.6 However, more recent findings have elucidated different assemblies of Aβ with varying degrees of toxic effects. β-Amyloid can exist as soluble monomers and oligomers, intermediate protofibrils, and insoluble fibrillar aggregates.7 Of these, soluble Aβ oligomers are potent synaptotoxins,8 and their concentration correlates with disease severity.9
Oligomers are small peptide polymers, and various toxic Aβ oligomers have been reported, ranging from dimers and trimers10 to 100mers.11 Nanomolar concentrations of Aβ oligomers strongly inhibit long-term potentiation (LTP),12,13 a leading experimental model for the synaptic changes underlying learning and memory. Recent evidence also suggests that synapse degeneration, likely central to the memory impairment in AD,14 first involves the single synaptic contact points between axons and dendrites found at dendritic spines.15 Consistent with their role in neurodegeneration, Aβ oligomers cause significant decrease in dendritic spine density in cultured hippocampal neurons.15 Behavioral assessments in rodents have confirmed these findings, complementing a growing number of in vitro investigations. β-Amyloid oligomers greatly impair spatial memory when administered to otherwise healthy rats.12,16
The concept of oligomeric Aβ synaptotoxins has helped strengthen the amyloid hypothesis. In transgenic mice, levels of specific Aβ oligomers closely match deficits in spatial memory,16 and clinically the amount of soluble Aβ in the brain correlates well with the degree of dementia.9 Moreover, Aβ oligomers isolated directly from human AD brains have been found to be equally toxic as synthetically derived Aβ.17 Despite these recent breakthroughs, the mechanisms by which Aβ oligomers exert their action have not been well understood. The effects on neurons are rapid and specific, and together the accumulated data have suggested the presence of a high-affinity Aβ oligomer receptor. This putative receptor would likely be central to the pathogenesis of AD and provide an attractive target for therapeutic intervention. Herein, we review the recent finding that cellular prion protein (PrPc) is a high-affinity binding site for Aβ oligomers, mediating their potent inhibitory effects on synaptic plasticity.11 We further discuss the association between PrPc and AD and the potential clinical relevance of these findings.
To detect Aβ oligomer binding sites, a biotin-tagged Aβ1-42 peptide was first synthesized.11 Biotin is frequently used as a molecular marker because of its extraordinarily high affinity for the protein avidin that, in turn, can be used for detection. The Aβ was oligomerized and applied to COS-7 cells expressing different complementary DNA (cDNA) obtained from an adult mouse brain library. At baseline, COS-7 cells show minimal binding of Aβ oligomers compared with hippocampal neurons, making these cells ideal for this type of screen. Biotin-Aβ oligomers potently bind hippocampal neurons, whereas monomeric Aβ does not, suggesting a necessary conformation of Aβ conferred by oligomerization.
Of 225 000 clones from the adult mouse cDNA library screened in the assay, 2 were found to bind biotin-Aβ oligomers. Both of these individual clones were subsequently shown to encode for full-length mouse PrPc. In addition to this unbiased genome-wide screen, a more specific library of known transmembrane proteins at lower stringency was assessed. As summarized in the Table, some were found to exhibit Aβ oligomer binding but with lesser affinity and selectivity than for PrPc. Several putative receptors for Aβ have previously been reported, including the receptor for advanced glycation end products,18 α7 nicotinic acetylcholine receptor,19 and tumor necrosis factor receptor 1.20 In the binding assay reviewed herein, only PrPc had high affinity and high specificity for Aβ oligomers.
Cellular prion protein is a glycosylphosphatidylinositol-linked extracellular membrane protein of approximately 250 amino acids that is abundantly expressed in the nervous system.21 It is likely best known to clinicians because of its role in human prion disease. Using PrPc deletion mutants, the exact binding site of Aβ oligomers was mapped to the region of amino acids 95 to 110. This area is within the unstructured central domain of PrPc (amino acids 95-134), which has been implicated in neuronal toxic effects in vitro22 and in extensive neurodegeneration in mice.23 α-Secretase, which cleaves APP within the Aβ domain (precluding the toxic Aβ peptide), also cleaves PrPc within its unstructured central domain at amino acids 110 to 111.24 Therefore, α-secretase may act to counter neurodegeneration by preventing the production of Aβ and by keeping potentially detrimental regions of PrPc in check. It is unknown whether cleavage of PrPc by α-secretase also affects Aβ oligomer binding.
To evaluate the functional role of the Aβ oligomer–×-PrPc interaction, the effects of Aβ oligomers on LTP were measured in brain sections from mice in which the PrPc gene was knocked out (PRNP–/–) (OMIM 176640). In wild-type hippocampal sections, a brief train of pulses in the theta frequency to Schaffer collateral fibers results in an increase in the excitatory postsynaptic potentials that can last for hours. This change in synaptic strength in response to a specific stimulus is believed to be a fundamental mechanism underlying learning and memory. When nanomolar concentrations of Aβ oligomers were applied to wild-type sections, LTP was strongly inhibited, as has been reported by numerous laboratories.10,13,17,20 In contrast, no inhibitory effects on LTP were seen when the same Aβ preparation was applied to brain sections from PRNP–/– animals, suggesting that Aβ oligomer signaling is mediated through PrPc.11 To confirm these findings, wild-type brain sections were pretreated with 6D11, a specific antibody to PrPc found to block Aβ oligomer binding. When these pretreated sections were exposed to the Aβ solution, LTP was unaffected, further suggesting a critical role of PrPc in Aβ oligomer–induced synaptotoxic effects.
Because PrPc is an extracellular protein, downstream Aβ oligomer signaling is likely mediated via a putative PrPc-associated transmembrane coreceptor (Figure). This putative coreceptor may have a critical role in AD-related neurodegeneration and, once identified, could provide an additional potential therapeutic target.
For at least a decade, an indirect association between AD and PrPc has been lingering in the literature. Early interest was fueled mostly by the fact that AD and human prion disease involve aggregates of pathologic proteins in the brain25 and that the amyloid precursor–like protein was reported to bind PrPc.26 Recently, more specific evidence has emerged linking PrPc to AD. From a genetic perspective, interest has been growing in the PRNP methionine/valine polymorphism (M129V) and its relationship to sporadic AD. Homozygosity at this codon, which is located within the unstructured central domain of PrPc, is associated with an increased risk of sporadic Creutzfeldt-Jakob disease.27 Others have found that this genotype confers an increased risk for sporadic AD in certain populations.28 Whether polymorphisms within the PRNP gene may affect Aβ oligomer binding to PrPc and alter susceptibility to AD is unknown, but it remains an intriguing possibility.
Cellular prion protein has also been reported to regulate APP processing by modulating β-secretase (BACE1) activity, but the results have been conflicting. Cells coexpressing APP and PrPc have a significant reduction in secreted Aβ compared with cells expressing APP alone.29 The region of PrPc responsible for this action was found to be in the N-terminus (amino acids 23-26), as no effects on BACE1 or Aβ levels were seen when this segment was removed.29 However, overexpressing PrPc in transgenic APP mice caused a modest increase of Aβ plaques in the brain,30 in contrast to the lowering effect of PrPc found in vitro. It is unclear whether binding of Aβ oligomers to PrPc might affect its proposed ability to regulate BACE1, setting up a potential feedback loop in response to Aβ levels, and this is an issue worth investigating further as the field moves forward.
In summary, we have reviewed the recent finding that PrPc functions as a high-affinity receptor to mediate the deleterious effects of Aβ oligomers on synaptic plasticity. Although much work remains to assess whether targeting PrPc or its putative coreceptor can be effective treatments in human AD, the potential is readily apparent. Cellular prior protein represents the first possible target in AD directly disrupting the signaling pathway of Aβ and might provide a more functional approach to relieving AD symptoms. Most important, modulating PrPc function does not seem to produce serious adverse effects, as PRNP knockout mice have minimal phenotypic changes and wild-type animals treated with PrPc antibodies do well. A large body of work on PrPc already exists because of its role in prion diseases. This knowledge could greatly facilitate drug discovery and our understanding of the downstream mechanisms of the Aβ oligomer–×-PrPc interaction.
Funding/Support: This study was supported by grants from the Cure Alzheimer's Fund, National Institutes of Health, and Falk Medical Research Trust (Dr Strittmatter).
Financial Disclosure: None reported.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Editor's Pick: Pineapple Papaya Facial Scrub
Typically, when you think of pineapple and papaya you'll conjure up an image complete with hammocks, beachside service, and fruity frozen cocktails topped with colorful umbrellas. However, after using Kiehl's Pineapple Papaya Facial Scrub, you'll likely have a whole new association in mind.
Made with real fruit extracts, this gentle facial scrub from Kiehl's offers exfoliation suitable for all skin types. Just like your favorite tropical beachside drinks, this scrub uses small pieces of actual pineapple and papaya fruit. Pineapple contains bromelain, a protein-digesting enzyme often used as a way to lightly break down dead skin cells which may have built up on your skin's surface. Thanks to the papaya, the scrub features papain, another protein- and dead skin cell-digesting enzyme. These enzymes work alongside finely ground scrub grains of luffa cylindrica fruit and apricot seed powder to remove built-up dead skin cells on the skin's surface which helps leave your skin feeling refreshed, soft, and clean. In addition to the gentle, yet effective, exfoliating power of the scrub, each use gives your skin a dose of vitamin oils to further enhance its soothing effects. Plus, sesame oil—from sesame seeds—features moisturizing emollient properties to help soften skin.
Just a small amount of the scrub is needed to exfoliate your entire face. Gently massage onto clean, damp skin in upward circular motions—avoiding the delicate eye area and concentrating on the T-zone. Let the scrub sit on your skin, without scrubbing, for up to two minutes to let the protein-digesting enzymes get to work. Remove with a damp, lukewarm soft facial cloth and follow up with your normal nightly skin care routine.Kiehl's Pineapple Papaya Facial Scrub, $28
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Agriculture Law involves farmers, landowners, and others in regards to crop-growing, farming processes, dairy production, livestock, farmland use, government subsidization of farming, and seasonal and migrant farm workers. There are numerous federal statutes that subsidize, regulate or otherwise directly affect agricultural activity. Some focusing on protecting migrant and seasonal agricultural workers, some for financial assistance to farmers and others for the construction or improvement of farm housing and other agriculturally related purposes.
Decatur is a city located in Wise County, Texas, United States. This city was named after Stephen Decatur, Jr. As of the 2007 census, the city had a total population of 15,478. It is the county seat of Wise County. Decatur is part of the Dallas/Fort Worth Metroplex and is located 25 miles northwest of Fort Worth and 45 miles northwest of Dallas. Decatur is one of the fastest growing cities in Texas, while Wise County is the fourth fastest growing county in Texas.
Agriculture Law Lawyers In Decatur Texas


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Sony Xperia Z2 and Xperia Z3 Android 6.0.1 Marshmallow Status Update
Sony continues to work on the delivery of Android 6.0 Marshmallow to a range of its devices. According to new reports, the company is now ready to roll out the Android 6.0.1 Marshmallow update iteration to its Xperia Z2 and Z3 series.
Sony owners with older unit models like the Xperia Z2 and the Xperia Z3 can now rejoice as the Android 6.0.1 Marshmallow update is now within reach. Previously, it was reported that Sony's Beta Program for the Android 6.0.1 Marshmallow update began for Sony Xperia Z2 and Xperia Z3. Fortunately for the latest update, more users will be part of the party and won't get left out in the cold.
According to Phone Arena, thanks to the newest update almost all of the devices under the Z2 and Z3 series will be updated to Marshmallow. This comes at a point when newer devices are always the first in line to get the update. Sony updates its Xperia Z5 series, Z4 Tablet and Xperia Z3+ series first before moving on to other devices. Additionally, users of Xperia Z3 (D6603), Xperia Z2 (D6503) and Xperia Z3 Compact (D5803) models were able to get the Marshmallow update earlier in the month given that they were part of the Beta Program.
According to Xperia Blog, Android 6.0.1 Marshmallow is now accessible to devices such as: Xperia Z2 (D6502, D6503), Xperia Z3 (D6603, D6646, D6653), Xperia Z3 Dual (D6633), Xperia Z3 Compact (D5803, D5833), and Xperia Z2 Tablet (SGP511, SGP512, SGP521). Users can expect the usual Marshmallow threats like Google Now on Tap, STAMINA mode, Sony Camera 2.0.0 and App Standby among others. As with other Android updates, users must connect to a reliable cellular or WiFi connection. They must also make sure that their devices are charged fully.
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Jean Dubost Laguiole Knives with Real Horn Handles, Set of 6 On Sale. On this review, we're going to uncover what's up while using . At an initial glance, it seems to have some quite sweet performance thinking about its price. If you're searching for top recommended , then Jean Dubost Laguiole Knives with Real Horn Handles, Set of 6 is the suggestion. Many good evaluations already proving the caliber of this product.
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Knives are built sometimes from forged or placed steel Forged knives are created from one little bit of steel that is heated and formed applying a hammer or press. Stamped knives are virtually "stamped" from one greater piece of metal. It was once a given that forged knives were higher quality, but that's no further true. These days, stamped knives are also manufactured to a very high quality common that's virtually indistinguishable from cast knives. Actually, many chefs choose stamped knives because they're light and more flexible, and they tend to carry their side more than softer, solid knives. Stamped knives are also much more affordable than forged ones.
Even though best knives will stvay sharp for a long time, many could eventually need to be sharpened. If that's anything you'd like to take on in the home, see our split report on knife sharpeners. But, if you think that could be over your level of expertise, you can find a nearby or mail-order qualified to complete the maintenance for you. All of the producers in that record may sharpen knives for the life of the knife for a small fee.
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"All on the Line with Joe Zee" featuring Adam Lambert. Pt 1: http://bit.ly/rVA5wm Pt 2:http://bit.ly/rC5D28 Pt 3: http://bit.ly/uU6rip#♒♎♈
Saturday, December 10, 2011
"All on the Line with Joe Zee" featuring Adam Lambert
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Domestic Violence and the Denver Community
Each year, more than 18,000 victims of domestic violence call SafeHouse Denver's hot line. Meet one of them.