Alzheimer's disease: inside, outside, upside down.
Neurotoxicity of beta-amyloid peptide (A beta) in Alzheimer's disease (AD) is usually thought to arise from the nonspecific effects of high concentrations of A beta on vulnerable neurons, resulting in membrane destabilization and increasing intracellular calcium concentration. This review advances the hypothesis that at early stages of AD, when A beta is present in lower amounts, its ability to perturb the function of cellular targets is mediated by specific cofactors present on the cell surface and intracellularly. Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor which binds A beta and amplifies its effects on cells in the nanomolar range. The intracellular enzyme A beta-binding alcohol dehydrogenase (ABAD) is likely to engage nascent A beta formed in the endoplasmic reticulum, and to mediate cell stress from this site. The analysis of A beta interaction with RAGE and ABAD, as well as other cofactors, provides insight into new mechanisms and, potentially, identifies therapeutic targets relevant to neuronal dysfunction in AD.
Yan
S D
SD
Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Schmidt
A M
AM
Stern
D
D
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008959:Models, Neurological; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000429:Alcohol Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; C458480:Hsd17b10 protein, mouse