Neurotoxicity of ϐ-amyloid peptide (Aϐ) in Alzheimer's disease (AD) is usually thought to arise from the nonspecific effects of high concentrations of Aϐ on vulnerable neurons, resulting in membrane destabilization and increasing intracellular calcium concentration. This review advances the hypothesis that at early stages of AD, when Aϐ 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 Aϐ and amplifies its effects on cells in the nanomolar range. The intracellular enzyme Aϐ-binding alcohol dehydrogenase (ABAD) is likely to engage nascent Aϐ formed in the endoplasmic reticulum, and to mediate cell stress from this site. The analysis of Aϐ 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.

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