Beta-Amyloid precursor protein mismetabolism and loss of calcium homeostasis in Alzheimer's disease.

Abstract

The suspected involvement of the beta-amyloid precursor protein (beta APP) in the etiology of Alzheimer's disease (AD) has been strengthened by recent genetic evidence, but pursuit of the mechanisms involved will initially require basic cell biology approaches. Several studies have concentrated on toxic activities of beta-amyloid peptide (beta AP) itself, illuminating its contributions to excitotoxicity and calcium-mediated degeneration in general. We now know that generation of beta AP from beta APP also compromises the production of an important set of trophic factors: the secreted forms of beta APP (APPS), which may act--ironically--by conferring protection from calcium-mediated insults. Therefore, conditions which contribute to the formation of beta AP (possibly including ischemia) not only produce an agent which exacerbates calcium-mediated cell death, but also reduce the levels of one of the few factors able to rescue calcium homeostasis. The implications of these postulates and their relationship to the process of aging are discussed.