Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

• Published in: The Journal of biological chemistry Vol. 285; no. 17; pp. 12463 - 12468
• Main Authors: Demuro, Angelo, Parker, Ian, Stutzmann, Grace E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-04-2010; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer Disease - therapy; Amyloid beta-Peptides - metabolism; Animals; Calcium; Calcium Signaling; Calcium/Channels; Cell Death; Cell/Apoptosis; Channels/Calcium; Diseases/Alzheimer Disease; Diseases/Amyloid; Homeostasis; Humans; Membrane/Channels; Minireviews; Molecular Bases of Disease; Peptides - metabolism; Peptides/Conformation; Receptors, Neurotransmitter - metabolism; Synapses - metabolism; Synapses - pathology; Calcium/Channels; Diseases/Alzheimer Disease; Membrane/Channels; Channels/Calcium; Calcium; Cell/Apoptosis; Diseases/Amyloid; Peptides/Conformation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.R109.080895

Intracellular Ca2+ signaling is fundamental to neuronal physiology and viability. Because of its ubiquitous roles, disruptions in Ca2+ homeostasis are implicated in diverse disease processes and have become a major focus of study in multifactorial neurodegenerative diseases such as Alzheimer disease (AD). A hallmark of AD is the excessive production of β-amyloid (Aβ) and its massive accumulation in amyloid plaques. In this minireview, we highlight the pathogenic interactions between altered cellular Ca2+ signaling and Aβ in its different aggregation states and how these elements coalesce to alter the course of the neurodegenerative disease. Ca2+ and Aβ intersect at several functional levels and temporal stages of AD, thereby altering neurotransmitter receptor properties, disrupting membrane integrity, and initiating apoptotic signaling cascades. Notably, there are reciprocal interactions between Ca2+ pathways and amyloid pathology; altered Ca2+ signaling accelerates Aβ formation, whereas Aβ peptides, particularly in soluble oligomeric forms, induce Ca2+ disruptions. A degenerative feed-forward cycle of toxic Aβ generation and Ca2+ perturbations results, which in turn can spin off to accelerate more global neuropathological cascades, ultimately leading to synaptic breakdown, cell death, and devastating memory loss. Although no cause or cure is currently known, targeting Ca2+ dyshomeostasis as an underlying and integral component of AD pathology may result in novel and effective treatments for AD.