Aberrant subcellular neuronal calcium regulation in aging and Alzheimer's disease

Simonetta Camandola, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

In this mini-review/opinion article we describe evidence that multiple cellular and molecular alterations in Alzheimer's disease (AD) pathogenesis involve perturbed cellular calcium regulation, and that alterations in synaptic calcium handling may be early and pivotal events in the disease process. With advancing age neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subcellular calcium dynamics. Altered proteolytic cleavage of the β-amyloid precursor protein (APP) in response to the aging process in combination with genetic and environmental factors results in the production and accumulation of neurotoxic forms of amyloid β-peptide (Aβ). Aβ undergoes a self-aggregation process and concomitantly generates reactive oxygen species that can trigger membrane-associated oxidative stress which, in turn, impairs the functions of ion-motive ATPases and glutamate and glucose transporters thereby rendering neurons vulnerable to excitotoxicity and apoptosis. Mutations in presenilin-1 that cause early-onset AD increase Aβ production, but also result in an abnormal increase in the size of endoplasmic reticulum calcium stores. Some of the events in the neurodegenerative cascade can be counteracted in animal models by manipulations that stabilize neuronal calcium homeostasis including dietary energy restriction, agonists of glucagon-like peptide 1 receptors and drugs that activate mitochondrial potassium channels. Emerging knowledge of the actions of calcium upstream and downstream of Aβ provides opportunities to develop novel preventative and therapeutic interventions for AD. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

Original languageEnglish (US)
Pages (from-to)965-973
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1813
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Keywords

  • Amyloid
  • Calcium channels
  • Cognitive impairment
  • Endoplasmic reticulum
  • GLP-1
  • Mitochondria

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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