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

M. P. Mattson

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)50-76
Number of pages27
JournalAnnals of the New York Academy of Sciences
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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