Interactions of Mitochondria/Metabolism and Calcium Regulation in Alzheimer’s Disease: A Calcinist Point of View

Abstract

Decades of research suggest that alterations in calcium are central to the pathophysiology of Alzheimer’s Disease (AD). Highly reproducible changes in calcium dynamics occur in cells from patients with both genetic and non-genetic forms of AD relative to controls. The most robust change is an exaggerated release of calcium from internal stores. Detailed analysis of these changes in animal and cell models of the AD-causing presenilin mutations reveal robust changes in ryanodine receptors, inositol tris-phosphate receptors, calcium leak channels and store activated calcium entry. Similar anomalies in calcium result when AD-like changes in mitochondrial enzymes or oxidative stress are induced experimentally. The calcium abnormalities can be directly linked to the altered tau phosphorylation, amyloid precursor protein processing and synaptic dysfunction that are defining features of AD. A better understanding of these changes is required before using calcium abnormalities as therapeutic targets.

Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas

“…First, ER-mitochondria connections regulate calcium homeostasis, which is well known to be altered in AD (167,176,177). Among its many functions, mitochondrial calcium buffering capacity regulates the intracellular concentration of calcium, not only by buffering local changes in the cytosol, but also via highly regulated contacts with the plasma membrane and/or the ER (178,179).…”

Ca2+, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases

“…The central role of Ca 2+ dysregulation in age-related memory deficits and neurodegenerative disease, proposed more than 30 years ago (Gibson and Peterson, 1987 ; Khachaturian, 1987 ; Landfield, 1987 ; Abdul et al, 2009 ), has been supported time and again by molecular, electrophysiological, biochemical and behavioral studies and is the subject of many excellent reviews (Alzheimer’s Association Calcium Hypothesis Workgroup, 2017 ; Frazier et al, 2017 ; Gibson and Thakkar, 2017 ; Pchitskaya et al, 2018 ). Neurons are often the focus of studies on Ca 2+ dysregulation, and for good reason.…”

Genetic and non-genetic factors associated with the phenotype of exceptional longevity & normal cognition

“…Interestingly, there was considerable overlap between the biochemical pathways identified in our study and the biochemical pathways associated with AD, notably immune system and inflammation 71,[74][75][76][77] . Calcium regulation is biological process involved with AD [78][79][80] and the RYR3 gene identified in our study is a key molecule involved in this process 81 . Lipid metabolism is a key pathway identified through pathway analysis of AD GWAS 71 and ESR1 polymorphisms have been shown to impact this pathway 82 , including lipid metabolism in the brain 83,84 .…”