Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity

Abstract

All forms of dementia including Alzheimer’s disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer’s disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and we suggest that it can also be protective against neurodegeneration and development of dementia. Using primary co-culture neurons and astrocytes we studied the effect of Tg-2112x and its derivative Tg-2113x on β-amyloid-induced changes in calcium signal, mitochondrial membrane potential, mitochondrial calcium, and cell death. We have found that both compounds had no effect on β-amyloid or acetylcholine-induced calcium changes in the cytosol although Tg2113x, but not Tg2112x reduced glutamate-induced calcium signal. Both compounds were able to reduce mitochondrial calcium uptake and protected cells against β-amyloid-induced mitochondrial depolarization and cell death. Behavioral effects of Tg-2113x on learning and memory in fear conditioning were also studied in 3 mouse models of neurodegeneration: aged (16-month-old) C57Bl/6j mice, scopolamine-induced amnesia (3-month-old mice), and 9-month-old 5xFAD mice. It was found that Tg-2113x prevented age-, scopolamine- and cerebral amyloidosis-induced decrease in fear conditioning. In addition, Tg-2113x restored fear extinction of aged mice. Thus, reduction of the mitochondrial calcium uptake protects neurons and astrocytes against β-amyloid-induced cell death and contributes to protection against dementia of different ethology. These compounds could be used as background for the developing of a novel generation of disease-modifying neuroprotective agents.

Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: A focused review

“…Other results demonstrate that the presence of misfolded tau protein blocks the efflux of calcium from mitochondria 49 . A more recent study also showed that inhibition of mitochondrial calcium uptake protects neurons and astrocytes against the effects of Aβ, including dementia 50 . Taken together, claims of altered mitochondrial Ca 2+ signalling as potential causative factors now explain the origin of neurodegeneration.…”

“…49 A more recent study also showed that inhibition of mitochondrial calcium uptake protects neurons and astrocytes against the effects of Aβ, including dementia. 50 Taken together, claims of altered mitochondrial Ca 2+ signalling as potential causative factors now explain the origin of neurodegeneration. However, insight into the precise consequences of the underlying molecular mechanisms and the longitudinal progression of the abnormalities needs further research.…”

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration

“…β-amyloid in aggregated form has been shown to be membrane-active and forms calcium channels in artificial membranes and in the membranes of astrocytes [48,49] as well as directly induces the opening of mPTP in experiments with isolated brain mitochondria [50,51]. In astrocytes, the combination of a β-amyloid-induced calcium signal and ROS overproduction has led to mitochondrial depolarization, which was dependent on CsA, inhibitors of mitochondrial calcium uptake, or it was blocked in astrocytes from CypD knockout mice [5,52,53].…”

“…Thus, despite the mitochondrial calcium overload, the inhibition of reactive oxygen species in NADPH oxidase, upon the application of β-amyloid, completely blocks mitochondrial depolarization [5]. However, the direct delivery of singlet oxygen to the mitochondria in live cells without mitochondrial calcium overload may not induce the opening of mPTP and cell death [53,63] (Figure 2).…”