Mitochondrial Calcium Signaling as a Therapeutic Target for Alzheimer’s Disease

Author(s): Aston J. Wu, Benjamin C.-K. Tong, Alexis S. Huang, Min Li, King-Ho Cheung*.

Journal Name: Current Alzheimer Research

Volume 17 , Issue 4 , 2020

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Abstract:

Mitochondria absorb calcium (Ca2+) at the expense of the electrochemical gradient generated during respiration. The influx of Ca2+ into the mitochondrial matrix helps maintain metabolic function and results in increased cytosolic Ca2+ during intracellular Ca2+ signaling. Mitochondrial Ca2+ homeostasis is tightly regulated by proteins located in the inner and outer mitochondrial membranes and by the cross-talk with endoplasmic reticulum Ca2+ signals. Increasing evidence indicates that mitochondrial Ca2+ overload is a pathological phenotype associated with Alzheimer’s Disease (AD). As intracellular Ca2+ dysregulation can be observed before the appearance of typical pathological hallmarks of AD, it is believed that mitochondrial Ca2+ overload may also play an important role in AD etiology. The high mitochondrial Ca2+ uptake can easily compromise neuronal functions and exacerbate AD progression by impairing mitochondrial respiration, increasing reactive oxygen species formation and inducing apoptosis. Additionally, mitochondrial Ca2+ overload can damage mitochondrial recycling via mitophagy. This review will discuss the molecular players involved in mitochondrial Ca2+ dysregulation and the pharmacotherapies that target this dysregulation. As most of the current AD therapeutics are based on amyloidopathy, tauopathy, and the cholinergic hypothesis, they achieve only symptomatic relief. Thus, determining how to reestablish mitochondrial Ca2+ homeostasis may aid in the development of novel AD therapeutic interventions.

Keywords: Calcium, Alzheimer's disease, mitochondria, hyperphosphorylation, neurodegenerative disorder, intracellular neurofibrillary tangles.

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Article Details

VOLUME: 17
ISSUE: 4
Year: 2020
Page: [329 - 343]
Pages: 15
DOI: 10.2174/1567205016666191210091302
Price: $65

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