Calcium signaling and amyloid toxicity in Alzheimer disease

Abstract

Intracellular Ca(2+) signaling is fundamental to neuronal physiology and viability. Because of its ubiquitous roles, disruptions in Ca(2+) 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 beta-amyloid (Abeta) and its massive accumulation in amyloid plaques. In this minireview, we highlight the pathogenic interactions between altered cellular Ca(2+) signaling and Abeta in its different aggregation states and how these elements coalesce to alter the course of the neurodegenerative disease. Ca(2+) and Abeta 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 Ca(2+) pathways and amyloid pathology; altered Ca(2+) signaling accelerates Abeta formation, whereas Abeta peptides, particularly in soluble oligomeric forms, induce Ca(2+) disruptions. A degenerative feed-forward cycle of toxic Abeta generation and Ca(2+) 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 Ca(2+) dyshomeostasis as an underlying and integral component of AD pathology may result in novel and effective treatments for AD.

FIGURE 1.

Schematic model for Aβ monomers in which misfolding triggers self-aggregation into dimers, trimers, oligomers, fibrils, and fibrillar aggregates or plaques. The Aβ aggregates formed by 2–50 monomers are considered the toxic species.

FIGURE 2.

Feed-forward Aβ peptide and Ca²⁺ signaling interactions. Aβ peptides interact with a variety of Ca²⁺ channels and sources (center, blue), often serving to up-regulate or aberrantly generate Ca²⁺ flux within the cell. This increase in Ca²⁺ from direct calcium channel alteration or through compromised lipid barriers can then serve to accelerate Aβ generation, thereby sustaining a pathogenic cycle. VGCC, voltage-gated Ca²⁺ channel.