Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity?

Abstract

Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca²⁺) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca²⁺ signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca²⁺ leak function of presenilins. Excessive ER Ca²⁺ release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2. Store-operated Ca²⁺ entry (nSOC) pathway is disrupted in AD spines due to downregulation of STIM2 protein. Because of these Ca²⁺ signaling abnormalities, a balance in activities of Ca²⁺-calmodulin-dependent kinase II (CaMKII) and Ca²⁺-dependent phosphatase calcineurin (CaN) is shifted at the synapse, tilting a balance between long-term potentiation (LTP) and long-term depression (LTD) synaptic mechanisms. As a result, synapses are weakened and eliminated in AD brains by LTD mechanism, causing memory loss. Targeting synaptic calcium signaling pathways offers opportunity for development of AD therapeutic agents.

Keywords: Alzheimer disease; Ca(2+) signaling; Ca(2+)-calmodulin-dependent kinase II (CaMKII); Calcineurin; Mushroom spines; Neuronal store-operated Ca(2+) channels; Ryanodine receptors; Synapse.