Early mitochondrial dysfunction proceeds neuroinflammation, synaptic alteration, and autophagy impairment in hippocampus of App knock-in Alzheimer mouse models

Naia, L.; Shimozawa, M.; Bereczki, E.; Li, X.; Liu, J.; Jiang, R.; Leal, N. S.; Pinho, C. M.; Berger, E.; Falk, V. L.; Dentoni, G.; Ankarcrona, M.; Nilsson, P.

doi:10.1101/2023.03.07.531542

bioRxiv · 10.1101/2023.03.07.531542

Early mitochondrial dysfunction proceeds neuroinflammation, synaptic alteration, and autophagy impairment in hippocampus of App knock-in Alzheimer mouse models

Naia, L.·Shimozawa, M.·Bereczki, E.·Li, X.·Liu, J.·Jiang, R.·Leal, N. S.·Pinho, C. M.·Berger, E.·Falk, V. L.·Dentoni, G.·Ankarcrona, M.·Nilsson, P.

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Abstract

Increased amyloid {beta}-peptide (A{beta}) level is one of the drivers of Alzheimers disease (AD). Amyloid precursor protein (App) knock-in mice recapitulate the human A{beta} pathology, allowing the elucidation of the downstream effects of A{beta} and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in the AppNL-F and AppNL-G-F knock-in mouse models by time-course transcriptome analysis of the hippocampus, a region severely affected in AD. Energy metabolism emerged as one of the most significantly altered pathways at an early stage of the development of the pathologies. Functional experiments in mitochondria isolated from AppNL-G-F brain subsequently identified upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, combined with higher susceptibility to Ca2+-overload. This was followed by a strong neuroinflammatory response and impaired autophagy. Accumulation of autophagosomes and reduced number of mitochondria content in presynaptic terminals could account for the altered synapse morphology including increased number of synaptic vesicles and lowered thickness of post synaptic density in AppNL-G-F mice. This shows that A{beta}-induced pathways in the App knock-in mice recapitulate some key pathologies observed in AD brain, and our data herein contributes to the understanding of their timewise appearance and potential role in new therapeutic approaches.

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Naia, L., Shimozawa, M., Bereczki, E., Li, X., Liu, J., Jiang, R., Leal, N. S., Pinho, C. M., Berger, E., Falk, V. L., Dentoni, G., Ankarcrona, M., Nilsson, P.. 2023-03-09. Early mitochondrial dysfunction proceeds neuroinflammation, synaptic alteration, and autophagy impairment in hippocampus of App knock-in Alzheimer mouse models. https://doi.org/10.1101/2023.03.07.531542

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