Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer disease

Norambuena, A.; Sagar, V. K.; Wang, Z.; Raut, P.; Feng, Z.; Wallrabe, H.; Pardo, E.; Kim, T.; Alam, S. R.; Hu, S.; Periasamy, A.; Bloom, G. S.

doi:10.1101/2024.02.02.578668

bioRxiv · 10.1101/2024.02.02.578668

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer disease

Norambuena, A.·Sagar, V. K.·Wang, Z.·Raut, P.·Feng, Z.·Wallrabe, H.·Pardo, E.·Kim, T.·Alam, S. R.·Hu, S.·Periasamy, A.·Bloom, G. S.

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Abstract

IntroductionReduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-{beta} oligomer (xcA{beta}O) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcA{beta}Os inhibit Nutrient-induced Mitochondrial Activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. MethodsBrain energy metabolism and oxygen consumption were recorded in APPSAA/+ mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. ResultsNiMA is inhibited in APPSAA/+ mice before other defects are detected in these amyloid-{beta}-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3{beta} signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3{beta} with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. ConclusionNiMA disruption in vivo occurs before histopathological changes and cognitive decline in APPSAA mice, and may represent an early stage in human AD.

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Norambuena, A., Sagar, V. K., Wang, Z., Raut, P., Feng, Z., Wallrabe, H., Pardo, E., Kim, T., Alam, S. R., Hu, S., Periasamy, A., Bloom, G. S.. 2024-02-04. Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer disease. https://doi.org/10.1101/2024.02.02.578668

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