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
Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain
Eloise Hudry,Jonathan Dashkoff,Allyson D. Roe,Shuko Takeda,Robert M. Koffie,Tadafumi Hashimoto,Maria Scheel,Tara L. Spires-Jones,Michal Arbel-Ornath,Rebecca A. Betensky,Beverly L. Davidson,Bradley T. Hyman +11 more
TL;DR: A differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aβ-mediated synaptotoxicity is shown, suggesting that the APOE genetic risk is mediated by Aβ, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.
Journal ArticleDOI
Noradrenergic Modulation of Cognition in Health and Disease
TL;DR: The unique role that norepinephrine plays in prefrontal cortical and hippocampal function and how its interaction with its various receptors contribute to cognitive behaviors are summarized.
Journal ArticleDOI
Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration
Manuel J. Santos,Rodrigo A. Quintanilla,Andrés Toro,Rodrigo A. Grandy,Margarita C. Dinamarca,Juan A. Godoy,Nibaldo C. Inestrosa +6 more
TL;DR: The data suggest, for the first time, a direct link between peroxisomal proliferation and neuroprotection from Aβ-induced degenerative changes.
Journal ArticleDOI
Role of the ubiquitin proteasome system in Alzheimer's disease.
TL;DR: Recent observations on possible links between the ubiquitin proteasome system and Alzheimer's disease are discussed, and the potential for utilizing UPS components as targets for treatment of this disease is discussed.
Journal ArticleDOI
Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein.
Toru Sato,Naoshi Dohmae,Yue Qi,Nobuto Kakuda,Hiroaki Misonou,Rie Mitsumori,Hiroko Maruyama,Edward H. Koo,Christian Haass,Koji Takio,Maho Morishima-Kawashima,Shoichi Ishiura,Yasuo Ihara +12 more
TL;DR: A link between the production of Aβ42 and CTFγ 49–99 is strongly suggested and an important insight is provided into the mechanisms of altered γ-cleavage caused by mtAPP and mtPS1/2.
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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