Calcium and neuronal injury in Alzheimer's disease. Contributions of beta-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 beta-peptide (A beta) 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 beta-amyloid precursor protein (beta APP), 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 beta APP (APPss) stabilize intracellular free calcium levels ([Ca2+]i) and protect neurons against excitotoxic insults. In contrast, A beta which arises from alternative processing of beta APP 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 (eg, beta APP mutations) of beta APP may increase the A beta/APPs 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 A beta 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 [Ca+]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 [Ca]i and protect neurons against excitotoxic injury and A beta toxicity. Age-related changes in the brain (eg, ischemic conditions, reduced glucose uptake, and increased glucocorticoid levels) may compromise the mechanisms that normally regulate [Ca2+]i adaptively.
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230.
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D000375:Aging; D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D018846:Excitatory Amino Acids / Q000502:physiology*; D005609:Free Radicals; D006706:Homeostasis; D006801:Humans; D009410:Nerve Degeneration; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018377:Neurotransmitter Agents / Q000502:physiology; D011499:Protein Processing, Post-Translational
D016564:Amyloid beta-Protein Precursor; D018846:Excitatory Amino Acids; D005609:Free Radicals; D018377:Neurotransmitter Agents; D002118:Calcium