Journal ArticleDOI
Alzheimer's Disease: Genes, Proteins, and Therapy
TLDR
Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.Abstract:
Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...read more
Citations
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Journal ArticleDOI
Interaction between human prion protein and amyloid-β (Aβ) oligomers role of N-terminal residues.
TL;DR: LaLauren et al. as discussed by the authors characterized the interaction between synthetic Aβ42 oligomers and the recombinant human prion protein (PrP) using two biophysical techniques: site-directed spin labeling and surface plasmon resonance.
Journal ArticleDOI
Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease β-amyloid
Kevin J. Barnham,Fredrik Haeffner,Giuseppe D. Ciccotosto,Cyril C. Curtain,Deborah J. Tew,Christine Mavros,Konrad Beyreuther,Darryl Carrington,Colin L. Masters,Robert A. Cherny,Roberto Cappai,Ashley I. Bush +11 more
TL;DR: Mutation of the tyrosine residue to alanine inhibited H2O2 production, Cu‐induced radicalization, dityrosine cross‐linking, and neurotoxicity, confirming the theoretical results.
Journal ArticleDOI
Mutations that Reduce Aggregation of the Alzheimer's Aβ42 Peptide: an Unbiased Search for the Sequence Determinants of Aβ Amyloidogenesis
TL;DR: A genetic screen that couples a readily observable phenotype in E. coli to the ability of a mutation in Abeta42 to reduce aggregation enabled the isolation of 36 variants of Abeta41 with reduced tendencies to aggregate, which are consistent with previous models implicating hydrophobic regions as determinants of AbETA42 aggregation.
Journal ArticleDOI
Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer's Disease
Jennifer L. Furman,Diana M. Sama,John C. Gant,Tina L. Beckett,M. Paul Murphy,Adam D. Bachstetter,Linda J. Van Eldik,Christopher M. Norris +7 more
TL;DR: A deleterious role for activated astrocytes in AD is confirmed and the groundwork for exploration of other novelAstrocyte-targeted therapeutics in an intact animal model of AD is laid for exploration.
Journal ArticleDOI
Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology.
TL;DR: Interestingly, glutamate not only influences amyloid ß production, but also amyloids ß can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression.
References
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Journal ArticleDOI
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Journal ArticleDOI
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