Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease

Abstract

Impairments in neuronal intracellular calcium (i Ca 2+) handling may contribute to Alzheimer's disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (m Ca 2+) signaling is a key regulator of both of these processes. Here, we report remodeling of the m Ca 2+ exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired m Ca 2+ efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na + /Ca 2+ exchanger (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology. Further, genetic rescue of neuronal NCLX in 3xTg-AD mice is sufficient to impede AD-associated pathology and memory loss. We show that m Ca 2+ overload contributes to AD progression by promoting superoxide generation, metabolic dysfunction and neuronal cell death. These results provide a link between the calcium dysregulation and metabolic dysfunction hypotheses of AD and suggest m Ca 2+ exchange as potential therapeutic target in AD.

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

“…Despite the lack of expected premature neurodegeneration in the STIM2/ORAI1 mice, our novel model can be a useful tool for further studies of the role of SOCE proteins in neurons. This is especially relevant in the context of conflicting evidence of STIM2 actions in neuronal pathophysiology [10,31,33,[48][49][50][51][52], the involvement of ORAI1 in neurotransmission [53] and the growing body of evidence that links Ca 2+ homeostasis to AD-related neurodegeneration.…”

“…Recent results by Jadiya and colleagues demonstrate that neuronal deletion of the mitochondrial Na + /Ca 2+ exchanger in 3xTg-AD mutant mice (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology [31]. The downregulation of NCLX protein levels was also observed in postmortem brain of patients with non-familial, sporadic AD.…”

“…The first one is that a sustained up-regulation of Ca 2+ has pathological consequences for neurons [11,30]. The second one is that the histopathological features of AD, such as deposition of Aβ, further increase Ca 2+ levels, thus accelerating the disease progression [14,31].Recent results by Jadiya and colleagues demonstrate that neuronal deletion of the mitochondrial Na + /Ca 2+ exchanger in 3xTg-AD mutant mice (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology [31]. The downregulation of NCLX protein levels was also observed in postmortem brain of patients with non-familial, sporadic AD.…”

“…The first one is that a sustained up-regulation of Ca 2+ has pathological consequences for neurons [11,30]. The second one is that the histopathological features of AD, such as deposition of Aβ, further increase Ca 2+ levels, thus accelerating the disease progression [14,31].…”

Editorial: Mitochondrial Dysfunction and Neurodegeneration

“…In vivo experiments have shown that Aβ plaque deposition promotes Ca 2+ overload and calcineurin activation, which leads to downstream synaptic and dendritic spine pathology (Kuchibhotla et al, 2008;Wu et al, 2010). Age-dependent alterations in mitochondrial Ca 2+ efflux accelerate memory deficits and increase both amyloidosis and tau hyperphosphorylation in 3xTg-AD mice (Jadiya et al, 2019). Rescue of the expression of NCLX (a critical component of the mitochondrial Na + /Ca 2+ exchange) in these mice restored cognitive function and attenuated hippocampal neuronal degeneration.…”