BETA-AMYLOID PRECURSOR PROTEIN METABOLITES AND LOSS OF NEURONAL CA2+ HOMEOSTASIS IN ALZHEIMERS-DISEASE

Recent findings link altered processing of beta-amyloid precursor protein (betaAPP) to disruption of neuronal Ca2+ homeostasis and an excitotoxic mechanism of cell death in Alzheimer's disease. A major pathway of betaAPP metabolism results in the release of secreted forms of betaAPP, APP(s)s. These secreted forms are released in response to electrical activity and can modulate neuronal responses to glutamate, suggesting roles in developmental and synaptic plasticity. BetaAPP is upregulated in response to neural injury and APP(s)s can protect neurons against excitotoxic or ischemic insults by stabilizing the intracellular Ca2+ concentration [Ca2+]i. An alternative betaAPP processing pathway liberates intact beta-amyloid peptide, which can form aggregates that disrupt Ca2+ homeostasis and render neurons vulnerable to metabolic or excitotoxic insults. Genetic abnormalities (e.g. certain betaAPP mutations or Down syndrome) and age-related changes in brain metabolism (e.g. reduced energy availability or increased oxidative stress) may favor accumulation of [Ca2+]i-destabilizing beta-amyloid peptide and diminish the release of [Ca2+]i-stabilizing, neuroprotective APP(s)s.