Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

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 neuro-degenerative diseases such as Alzheimer disease (AD). A hallmark of AD is the excessive production of beta-amyloid (A beta) and its massive accumulation in amyloid plaques. In this minireview, we highlight the pathogenic interactions between altered cellular Ca2+ signaling and A beta in its different aggregation states and how these elements coalesce to alter the course of the neurodegenerative disease. Ca2+ and A beta 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 A beta formation, whereas A beta peptides, particularly in soluble oligomeric forms, induce Ca2+ disruptions. Adegenerative feed-forward cycle of toxic A beta 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.