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Ebselen Interferes with Alzheimer's Disease by Regulating Mitochondrial Function.

ABSTRACT: (1) Background: With unknown causes and no effective treatment available, Alzheimer's disease (AD) places enormous pressure on families and society. Our previous study had shown that Ebselen at a high concentration (10.94 μM) improved the cognition of triple-transgenic AD (3×Tg-AD) mice and alleviated the related pathological indicators but showed toxicity to the mice. Here, we dedicated to study the therapeutic effect and molecular mechanism of Ebselen at a much lower concentration on 3×Tg-AD mice. (2) Methods: Various behavioral experiments were applied to detect the behavioral ability of mice. Western blot, thioflavin T staining and a transmission electron microscope were used to evaluate the pathology of AD mice. The mitochondrial membrane potential and respiration were assessed with the corresponding assay kit. (3) Results: Ebselen remarkably increased cognitive ability of AD mice, eliminated β-Amyloid (Aβ) oligomers and recovered the synaptic damage in AD mice brain. In addition, the destroyed mitochondrial morphologies and function were repaired by Ebselen through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in N2a-SW cells and brain tissues of AD mice. (4) Conclusions: This research indicated that Ebselen might exert its therapeutic effect via protecting mitochondria in AD.

SUBMITTER: Li X

PROVIDER: S-EPMC9312019 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mitochondrial dysfunction and oxidative stress are frequently observed in the early stages of Alzheimer's disease (AD). Studies have shown that presenilin-1 (PS1), the catalytic subunit of γ-secretase whose mutation is linked to familial AD (FAD), localizes to the mitochondrial membrane and regulates its homeostasis. Thus, we investigated how five PS1 mutations (A431E, E280A, H163R, M146V, and Δexon9) observed in FAD affect mitochondrial functions. Methods: We used H4 glioblastoma cell lines genetically engineered to inducibly express either the wild-type PS1 or one of the five PS1 mutants in order to examine mitochondrial morphology, dynamics, membrane potential, ATP production, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), oxidative stress, and bioenergetics. Furthermore, we used brains of PS1M146V knock-in mice, 3xTg-AD mice, and human AD patients in order to investigate the role of PS1 in regulating MAMs formation. Results: Each PS1 mutant exhibited slightly different mitochondrial dysfunction. Δexon9 mutant induced mitochondrial fragmentation while A431E, E280A, H163R, and M146V mutants increased MAMs formation. A431E, E280A, M146V, and Δexon9 mutants also induced mitochondrial ROS production. A431E mutant impaired both complex I and peroxidase activity while M146V mutant only impaired peroxidase activity. All PS1 mutants compromised mitochondrial membrane potential and cellular ATP levels were reduced by A431E, M146V, and Δexon9 mutants. Through comparative profiling of hippocampal gene expression in PS1M146V knock-in mice, we found that PS1M146V upregulates Atlastin 2 (ATL2) expression level, which increases ER-mitochondria contacts. Down-regulation of ATL2 after PS1 mutant induction rescued abnormally elevated ER-mitochondria interactions back to the normal level. Moreover, ATL2 expression levels were significantly elevated in the brains of 3xTg-AD mice and AD patients. Conclusions: Overall, our findings suggest that each of the five FAD-linked PS1 mutations has a deleterious effect on mitochondrial functions in a variety of ways. The adverse effects of PS1 mutations on mitochondria may contribute to MAMs formation and oxidative stress resulting in an accelerated age of disease onset in people harboring mutant PS1.

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Ebselen Interferes with Alzheimer's Disease by Regulating Mitochondrial Function.

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