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
The Amyloid β Peptide (Aβ1-40) Is Thermodynamically Soluble at Physiological Concentrations†
TL;DR: Using fluorescence correlation spectroscopy, Wang et al. as mentioned in this paper showed that Aβ1-40 precipitates in vitro only if the dissolved concentration is > 14 μM, after which the size distribution of Aβ monomer/oligomers in the solution phase becomes stationary in time and independent of the starting Aβ concentration.
Journal ArticleDOI
Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease.
TL;DR: The role of astrocytes as active Aβ clearing cells in the CNS that may have important implications for future development of therapeutic strategies for AD is supported.
Journal ArticleDOI
Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimer's disease risk?
TL;DR: The cytoplasmic C-terminus of APP plays critical roles in its cellular trafficking and delivery to proteases, and compounds that modulate APP-adaptor protein interactions may inhibit Abeta generation by specifically targeting the substrate (APP) instead of the enzyme (beta- or gamma-secretase).
Journal ArticleDOI
The in Vivo Brain Interactome of the Amyloid Precursor Protein
Yu Bai,Kelly Markham,Fusheng Chen,Rasanjala Weerasekera,Joel C. Watts,Patrick Horne,Yosuke Wakutani,Rick D. Bagshaw,Paul M. Mathews,Paul E. Fraser,David Westaway,Peter St George-Hyslop,Peter St George-Hyslop,Gerold Schmitt-Ulms +13 more
TL;DR: The application of time-controlled transcardiac perfusion cross-linking for the in vivo mapping of protein interactions in intact tissue to study the interactome of the amyloid precursor protein (APP) confirmed eight previously reported interactions and revealed the identity of more than 30 additional proteins that reside in spatial proximity to APP in the brain.
Journal ArticleDOI
The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation.
TL;DR: 4-HNE accelerates the formation of Abeta protofibrils while inhibiting the production of straight, mature fibrils, providing further incentive to understand the role of oxidative stress and small-molecule Abeta modifications in sporadic AD.
References
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Journal ArticleDOI
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Elizabeth H. Corder,Ann M. Saunders,Warren J. Strittmatter,Donald E. Schmechel,P. C. Gaskell,Gary W. Small,A. D. Roses,Jonathan L. Haines,Margaret A. Pericak-Vance +8 more
TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Journal ArticleDOI
Notch Signaling: Cell Fate Control and Signal Integration in Development
TL;DR: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development, providing a general developmental tool to influence organ formation and morphogenesis.
Journal ArticleDOI
Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein
George G. Glenner,Caine W. Wong +1 more
TL;DR: A purified protein derived from the twisted beta-pleated sheet fibrils in cerebrovascular amyloidosis associated with Alzheimer's disease has been isolated and Amino acid sequence analysis and a computer search reveals this protein to have no homology with any protein sequenced thus far.
Journal ArticleDOI
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Jie Kang,H. G. Lemaire,A. Unterbeck,J. M. Salbaum,Colin L. Masters,K.-H. Grzeschik,Gerd Multhaup,Konrad Beyreuther,Benno Müller-Hill +8 more
TL;DR: An apparently full-length complementary DNA clone coding for the A4 polypeptide is isolated and sequenced and suggests that the cerebral amyloid deposited in Alzheimer's disease and aged Down's syndrome is caused by aberrant catabolism of a cell-surface receptor.
Journal ArticleDOI
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
Alison Goate,Marie-Christine Chartier-Harlin,Michael Mullan,Jeremy P Brown,Fiona Crawford,Liana Fidani,L. Giuffra,Andrew Haynes,N.G. Irving,Louise James,R. Mant,Phillippa Newton,Karen Rooke,P Roques,Christopher Talbot,Margaret A. Pericak-Vance,Alien D. Roses,Robert Williamson,Martin N. Rossor,Michael John Owen,John Hardy +20 more
TL;DR: A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene as discussed by the authors, which suggests that some cases of AD could be caused by mutations in the APP gene.
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