International journal of biological sciences · 2026
APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.
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Yen Yu-Hsin, Yuan Fang, Tang Daijiao, Luo Jing-Fang, Ming Chen, Kang Phil-Jun, Su Huanxing, Chong Cheong-Meng, Zhang Su-Chun
Аннотация
BACKGROUND: Mitochondrial dysfunction is widely regarded as a central and early feature of Alzheimer's disease (AD) pathology. Prior studies suggest that the accumulation of amyloid precursor protein (APP) within mitochondria contributes to this dysfunction. Mutations in presenilin-1 (PS1), which account for most cases of early-onset familial AD (FAD), have also been shown to impair mitochondrial function. In this study, we investigated how APP influences PS1 mutation-induced mitochondrial dysfunction in human cortical neurons derived from patient induced pluripotent stem cells (iPSCs).
METHODS: We analyzed transcriptomic and proteomic datasets from postmortem sporadic AD cortex to identify key dysregulated pathways. To functionally interrogate selected mechanisms, we established a panel of CRISPR/Cas9-engineered human iPSC lines, including PS1 mutant lines (PS1+/F105C and PS1+/A246E), an APP knockout derivative (APP-/-_PS1+/F105C), and their isogenic wild-type controls. These iPSCs were differentiated into cortical neurons for functional studies. Following directed differentiation into cortical neurons, biochemical analyses and super-resolution imaging were conducted to evaluate mitochondrial and neuronal phenotypes.
RESULTS: Analyses of sporadic AD cortical transcriptomes and proteomes identified mitochondrial dysfunction as a prominently altered pathway. In agreement, cortical neurons differentiated from FAD PS1 mutant (F105C and A246E) iPSCs displayed mitochondrial defects and AD-related phenotypes, both of which were mitigated by APP knockout.
CONCLUSIONS: These findings provide critical insights into the bridging role of APP in FAD PS1 mutant-mediated mitochondrial dysfunction, advancing our understanding of the cellular mechanisms underlying AD.
METHODS: We analyzed transcriptomic and proteomic datasets from postmortem sporadic AD cortex to identify key dysregulated pathways. To functionally interrogate selected mechanisms, we established a panel of CRISPR/Cas9-engineered human iPSC lines, including PS1 mutant lines (PS1+/F105C and PS1+/A246E), an APP knockout derivative (APP-/-_PS1+/F105C), and their isogenic wild-type controls. These iPSCs were differentiated into cortical neurons for functional studies. Following directed differentiation into cortical neurons, biochemical analyses and super-resolution imaging were conducted to evaluate mitochondrial and neuronal phenotypes.
RESULTS: Analyses of sporadic AD cortical transcriptomes and proteomes identified mitochondrial dysfunction as a prominently altered pathway. In agreement, cortical neurons differentiated from FAD PS1 mutant (F105C and A246E) iPSCs displayed mitochondrial defects and AD-related phenotypes, both of which were mitigated by APP knockout.
CONCLUSIONS: These findings provide critical insights into the bridging role of APP in FAD PS1 mutant-mediated mitochondrial dysfunction, advancing our understanding of the cellular mechanisms underlying AD.