Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function

Abstract

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.

Molecular Signatures of Mitochondrial Complexes Involved in Alzheimer’s Disease via Oxidative Phosphorylation and Retrograde Endocannabinoid Signaling Pathways

“…NDUFAB1, a subunit of the NADH: ubiquinone oxidoreductase (NQR), encodes the initial enzyme of the mitochondrial respiratory chain (i.e., complex I) that catalyzes the transport of electrons from NADH to ubiquinone for ATP synthesis [ 68 ]. In Parkinson's disease [ 69 ] and AD [ 70 ], deficiency of complex I inhibits the activity of the electron transport chain, rendering it unable to cope with increased oxidative stress, leading to a pattern of programmed cell death termed as apoptosis. This is validated by administration of 1-methyl-4-phenylpyridinium ion (MPP1), an inhibitor of complex I, eliciting internucleosomal DNA degradation and inappropriate apoptotic activation in cultured PC12 and cerebellar granule cells [ 71 ].…”

Therapeutic effects of total saikosaponins from Radix bupleuri against Alzheimer’s disease

“…APP is a single-pass transmembrane protein expressed in high levels in the brain, and three enzymes are responsible for cleaving APP: α-secretase, BACE1, and γ-secretase ( Lee et al, 2016 ). Aβ, a derivative of APP, is primarily produced by sequential cleavage of BACE1 and γ-secretase, and deposited in the brains of AD patients in the form of plaques ( Lee et al, 2016 ; Jiang et al, 2020 ; Han et al, 2021 ; Ledo et al, 2021 ). Increased concentration and activity of BACE1 was also observed in AD brain and body fluids ( Lee et al, 2016 ; Hampel et al, 2021 ).…”

Mitochondrial Ca2+ Signaling and Bioenergetics in Alzheimer’s Disease

“…Different AD models display an increased physical interaction between ER and mitochondrion [ 123 , 151 , 153 , 154 , 155 , 156 ], even before Aβ plaque deposition [ 123 , 157 ], although other reports indicate a decrease in ER-mitochondria contact sites in cells treated with Aβ oligomers [ 158 ], or no effect by the expression of PSEN1 mutations [ 153 ]. Generally, it has been demonstrated that there is a positive correlation between the number of ER-mitochondria contacts and aging [ 159 ].…”