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

Abstract

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.

A Review of Bile Acid Metabolism and Signaling in Cognitive Dysfunction-Related Diseases

“…With continuous studies, it is considered that the main pathogenesis of AD includes the degeneration of Aβ [90][91][92], hyperphosphorylation of Tau protein [93], the imbalance of choline [94], neuroinflammation [95,96], abnormalities in neurotransmitters, and dysfunction of mitochondrial autophagy [97,98]. In addition, recent studies have revealed that gut microbiota dysregulation [99,100] and Ca2+ influx [101,102] are also closely associated with AD.…”

Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer’s Disease

“…It is characterized by extracellular accumulation of amyloid plaques and intraneuronal tau neurofibrillary tangles causing loss of synapses and synaptic plasticity, thus impairing learning and memory [2][3][4][5]. It is further known that alterations in the homeostasis of glutamate and other ions such as Ca 2+ are involved in the pathogenesis of AD [5,6].…”

Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A

“…Aβ cascades have been proposed as triggers for excitotoxity in AD. [51][52][53] The proposition, however, cannot account for how neurodegeneration could develop before Aβ-related pathologies in many AD cases. Our investigation is an initial effort to reveal the primary pathogenic mechanism mediated by continual hyperactivities of NMDAR in the deficiency of its unique inhibitory subunit GluN3A.…”