Theranostics 2021; 11(18):8855-8873. doi:10.7150/thno.59776 This issue

Research Paper

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

Jihoon Han1, Heejin Park1, Chinmoyee Maharana2,3, A-Ryeong Gwon1, Jinsu Park1, Seung Hyun Baek1, Han-Gyu Bae1, Yoonsuk Cho1, Hark Kyun Kim1, Jae Hoon Sul1, Jeongmi Lee1, Eunae Kim1, Junsik Kim1, Yongeun Cho1, Sunyoung Park1, Leon F. Palomera1, Thiruma V. Arumugam1,4, Mark P. Mattson5✉, Dong-Gyu Jo1,6,7✉

1. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
2. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
3. Department of Zoology, University of Jammu, Jammu Tawi - 180006, India.
4. School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia.
5. Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
6. Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea.
7. Biomedical Institute for Convergence, Sungkyunkwan University, Suwon 16419, Korea.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Han J, Park H, Maharana C, Gwon AR, Park J, Baek SH, Bae HG, Cho Y, Kim HK, Sul JH, Lee J, Kim E, Kim J, Cho Y, Park S, Palomera LF, Arumugam TV, Mattson MP, Jo DG. Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function. Theranostics 2021; 11(18):8855-8873. doi:10.7150/thno.59776. Available from

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Graphic 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.

Keywords: Alzheimer's disease, Presenilin-1, Mitochondria, MAMs, ATL2