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PMID: 20413848 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease.

Journal of Alzheimer's disease : JAD ·Vol. 20 Suppl 2 ·2010-00-00 ·Pages S487-98

Supnet C, Bezprozvanny I

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the aged worldwide. AD is characterized by extensive synaptic and neuronal loss that leads to impaired memory and cognitive decline. The cause of AD is not completely understood and no effective therapy has been developed. The accumulation of toxic amyloid-beta42 (Abeta42) peptide oligomers and aggregates in AD brain has been proposed to be primarily responsible for the pathology of the disease, an idea dubbed the 'amyloid hypothesis' of AD etiology. In addition to the increase in Abeta42 levels, disturbances in neuronal calcium (Ca2+) signaling and alterations in expression levels of Ca2+ signaling proteins have been observed in animal models of familial AD and in studies of postmortem brain samples from sporadic AD patients. Based on these data, the 'Ca2+ hypothesis of AD' has been proposed. In particular, familial AD has been linked with enhanced Ca2+ release from the endoplasmic reticulum and elevated cytosolic Ca2+ levels. The augmented cytosolic Ca2+ levels can trigger signaling cascades that affect synaptic stability and function and can be detrimental to neuronal health, such as activation of calcineurin and calpains. Here we review the latest results supporting the 'Ca2+ hypothesis' of AD pathogenesis. We further argue that over time, supranormal cytosolic Ca2+ signaling can impair mitochondrial function in AD neurons. We conclude that inhibitors and stabilizers of neuronal Ca2+ signaling and mitochondrial function may have therapeutic potential for AD treatment. We also discuss latest and planned AD therapeutic trials of agents targeting Ca2+ channels and mitochondria.

MeSH Terms
Alzheimer Disease/drug therapy,etiology,pathology Animals Calcium Channel Blockers/therapeutic use Calcium Signaling/physiology Humans Mitochondrial Diseases/complications,drug therapy,pathology Models, Biological Neurons/metabolism
Chemicals
Calcium Channel Blockers
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Supnet Charlene
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Bezprozvanny Ilya
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Article Info
Journal
Journal of Alzheimer's disease : JAD
Abbr.
J Alzheimers Dis
ISSN
1875-8908
DOI
10.3233/JAD-2010-100306
Published
2010-00-00
Pages
S487-98
Language
English
Region
Netherlands
NLM ID
9814863
PMCID
PMC4996661
Subset
IM
Grants
NIA NIH HHS · R01 AG030746 · United States
NIA NIH HHS · R01AG030746 · United States
External Links
PubMed source DOI: 10.3233/JAD-2010-100306 PMC Full Text View journal details
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