Ca²⁺ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease

• Main Authors: John McDaid, Sarah Mustaly-Kalimi, Grace E. Stutzmann
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Cells
• Subjects: calcium; synaptic; glutamate; nicotinic receptors; mitochondria; autophagy
• Online Access: https://www.mdpi.com/2073-4409/9/12/2655

Ca²⁺ homeostasis is essential for multiple neuronal functions and thus, Ca²⁺ dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca²⁺ mishandling in AD, the cellular basis for loss of cognitive function remains under investigation. The process of synaptic degradation and degeneration in AD is slow, and constitutes a series of maladaptive processes each contributing to a further destabilization of the Ca²⁺ homeostatic machinery. Ca²⁺ homeostasis involves precise maintenance of cytosolic Ca²⁺ levels, despite extracellular influx via multiple synaptic Ca²⁺ channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP₃R, lysosomes via transient receptor potential mucolipin channel (TRPML) and two pore channel (TPC), and mitochondria via the permeability transition pore (PTP). Furthermore, functioning of these organelles relies upon regulated inter-organelle Ca²⁺ handling, with aberrant signaling resulting in synaptic dysfunction, protein mishandling, oxidative stress and defective bioenergetics, among other consequences consistent with AD. With few effective treatments currently available to mitigate AD, the past few years have seen a significant increase in the study of synaptic and cellular mechanisms as drivers of AD, including Ca²⁺ dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments.