Calcium and neuronal injury in Alzheimer's disease: Contributions of β-amyloid precursor protein mismetabolism, free radicals, and metabolic compromise

Alzheimer's disease (AD) is defined by degeneration of specific populations of neurons and the presence of insoluble aggregates of cytoskeletal proteins and amyloid β-peptide (Aβ) within affected brain regions. Alzheimer's disease does not appear to result from a single alteration, but in some cases of inherited AD a specific genetic defect can precipitate the disease. In this article, metabolic compromise, altered metabolism of the β-amyloid precursor protein (βAPP), and an excitotoxic form of neuronal injury are considered central to the pathogenesis AD. The hypothesis is forwarded that destabilization of neuronal Ca²⁺ homeostasis underlies neuronal degeneration and that multiple age-associated and/or genetic alterations contribute to the loss of Ca²⁺ homeostasis. Recent studies showed that the secreted forms of βAPP (APP(s)s) stabilize intracellular free calcium levels ([Ca²⁺](i)) and protect neurons against excitotoxic insults. In contrast, Aβ which arises from alternative processing of βAPP forms free radical peptides and aggregates that destabilize [Ca²⁺](i) and make neurons vulnerable to metabolic insults. Increased expression (eg, Down's syndrome) or altered processing leg, βAPP mutations) of βAPP may increase the Aβ/APP(s) ratio. The death of neurons in AD most likely has an excitotoxic component because: the vulnerable neurons possess high levels of glutamate receptors; experimentally induced excitotoxicity shows several features similar to those of neurofibrillary tangles; and Aβ can destabilize [Ca²⁺](i) homeostasis and render neurons vulnerable to neurofibrillary degeneration. Selective vulnerability may result from cell type-specific differences in expression of proteins involved in regulating [Ca²⁺](i). In addition, many intercellular signals are involved in determining whether a neuron is able to maintain [Ca²⁺](i) within a range of concentrations conducive to cell survival and adaptive plasticity. In this regard, it was recently shown that several growth factors can stabilize [Ca²⁺](i) and protect neurons against excitotoxic injury and Aβ toxicity. Age-related changes in the brain leg, ischemic conditions, reduced glucose uptake, and increased glucocorticoid levels) may compromise the mechanisms that normally regulate [Ca²⁺](i) adaptively.