Alzheimer's Disease
Open Access
- 16 May 2011
- journal article
- review article
- Published by Cold Spring Harbor Laboratory in Cold Spring Harbor Perspectives in Biology
- Vol. 3 (7), a004457
- https://doi.org/10.1101/cshperspect.a004457
Abstract
Over the last three decades, advances in biochemical pathology and human genetics have illuminated one of the most enigmatic subjects in biomedicine—neurodegeneration. Eponymic diseases of the nervous system such as Alzheimer's, Parkinson's, and Huntington's diseases that were long characterized by mechanistic ignorance have yielded striking progress in our understanding of their molecular underpinnings. A central theme in these and related disorders is the concept that certain normally soluble neuronal proteins can misfold and aggregate into oligomers and amyloid fibrils which can confer profound cytotoxicity. Perhaps the foremost example, both in terms of its societal impact and how far knowledge has moved toward the clinic, is that of Alzheimer's disease (AD). Here, we will review the classical protein lesions of the disorder that have provided a road map to etiology and pathogenesis. We will discuss how elucidating the genotype-to-phenotype relationships of familial forms of Alzheimer's disease has highlighted the importance of the misfolding and altered proteostasis of two otherwise soluble proteins, amyloid β-protein and tau, suggesting mechanism-based therapeutic targets that have led to clinical trials.Keywords
This publication has 100 references indexed in Scilit:
- Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genesEMBO Reports, 2006
- Natural oligomers of the amyloid-β protein specifically disrupt cognitive functionNature Neuroscience, 2004
- Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's DiseaseThe American Journal of Pathology, 1999
- Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesodermNature, 1997
- Amyloid β protein (Aβ) deposition in chromosome 14–linked Alzheimer's disease: Predominance of Aβ42(43)Annals of Neurology, 1996
- β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activityCell, 1995
- Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.Proceedings of the National Academy of Sciences of the United States of America, 1993
- Amyloid A4 Protein and Its Precursor in Down's Syndrome and Alzheimer's DiseaseNew England Journal of Medicine, 1989
- Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril proteinBiochemical and Biophysical Research Communications, 1984
- Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid proteinBiochemical and Biophysical Research Communications, 1984