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bioRxiv · 10.1101/2024.06.24.600414

Mitochondrial Dynamics and Bioenergetics in iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations

MacMullen, C. M.·Sharma, N.·Davis, R. L.
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Abstract

Mitochondrial (MT) dysfunction is a hallmark of Alzheimers Disease (AD), but the specific defects across forms of AD are unknown. We measured multiple parameters of MT dynamics and function, and neurite degeneration, in iPSC-derived human neurons possessing natural and engineered mutations in PS1, PS2, and APP genes. Mutations in all three genes altered MT function measured by basal, ATP-linked, and maximal oxygen consumption rate; and spare respiratory capacity, with PS1/PS2 alleles being more severe than APP mutations. Electron flow through Complexes I-IV was decreased in PS1/PS2 mutations but; in contrast, APP alleles had only modest impairments of CI and CII. We measured aspects of MT dynamics including fragmentation, and neurite degeneration, both of which were dramatic in PS1/PS2 alleles, but essentially absent in APP alleles. The marked differences in MT pathology may occur from the distinct ways APP is processed into A{beta} and may correlate with the disease severity.

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MacMullen, C. M., Sharma, N., Davis, R. L.. 2024-06-28. Mitochondrial Dynamics and Bioenergetics in iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. https://doi.org/10.1101/2024.06.24.600414

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