β-Amyloid precursor protein metabolites and loss of neuronal Ca 2+ homeostasis in Alzheimer's disease

Abstract

Recent findings link altered processing of β-amyloid precursor protein (βAPP) to disruption of neuronal Ca 2+ homeostasis and an excitotoxic mechanism of cell death in Alzheimer's disease. A major pathway of βAPP metabolism results in the release of secreted forms of βAPP, APP ss. These secreted forms are released in response to electrical activity and can modulate neuronal responses to glutamate, suggesting roles in developmental and synaptic plasticity. βAPP is upregulated in response to neural injury and APP ss can protect neurons against excitotoxic or ischemic insults by stabilizing the intracellular Ca 2+ concentration [Ca 2+] i. An alternative βAPP processing pathway liberates intact β- amyloid peptide, which can form aggregates that disrupt Ca 2+ homeostasis and render neurons vulnerable to metabolic or excitotoxic insults. Genetic abnormalities (e.g. certain βAPP mutations or Down syndrome) and age-related changes in brain metabolism (e.g. reduced energy availability or increased oxidative stress) may favor accumulation of [Ca 2+ i-destabilizing β- amyloid peptide and diminish the release of [Ca 2+] i-stabilizing, neuroprotective APP ss.