Hampered AMPK-ULK1 cascade in Alzheimer disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin

Mary, A.; Barale, S.; Eysert, F.; Valverde, A.; Lacas-Gervais, S.; Bauer, C.; Eddarkaou, S.; Buee, L.; Buee-Scherrer, V.; Checler, F.; Chami, M.

doi:10.1101/2024.12.28.630598

bioRxiv · 10.1101/2024.12.28.630598

Hampered AMPK-ULK1 cascade in Alzheimer disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin

Mary, A.·Barale, S.·Eysert, F.·Valverde, A.·Lacas-Gervais, S.·Bauer, C.·Eddarkaou, S.·Buee, L.·Buee-Scherrer, V.·Checler, F.·Chami, M.

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Abstract

BackgroundMitochondrial structure and function alterations are key pathological features in Alzheimers disease (AD) brains. The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key node controlling mitochondria health, the alteration of which likely contribute to AD development. MethodsWe designed this study to investigate AMPK-ULK1 activation state in post-mortem human sporadic AD brains, in 3xTgAD mice that recapitulate most of human AD features, and in neuronal cells expressing the amyloid precursor protein with the familial Swedish mutation (APPswe). We examined the impact of the pharmacological and genetic modulation of AMPK-ULK1 cascade on mitochondria structure and functions in APPswe cells. We evaluated the potential beneficial impact of AMPK-ULK1 activation by Metformin (Met) on mitochondria defects, as well as on early- and late-stage AD-related alterations in vivo and ex vivo. ResultsAt first, we show that AMPK-ULK1 cascade is defective in murine and human AD brains as well as in APPswe cells. We then report that Met administration to 3xTgAD mice alleviates the alterations of neuronal mitochondria structure and function and we consolidate these results in cells using both pharmacological and genetic tools to modulate AMPK-ULK1 cascade. In mice brains, Met reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as the amyloid beta (A{beta}) burden present in aged mice. Mechanistically, we show that Met increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments in vivo and enhances cathepsin D activity in vitro. The reduction of A{beta} load by Met occurs through an increased recruitment of Iba1+ cells to A{beta} plaques and an enhancement of the phagocytic activity of microglia. Accordingly, in symptomatic 3xTgAD mice, Met alleviates microgliosis and astrogliosis, modulates microglia morphology, reduces peripheral proinflammatory cytokines levels, and regulates the expression of a set of inflammatory genes. In addition, Met normalizes dendritic spines shape in organotypic hippocampal slice cultures modeling AD and improves learning performance of 3xTgAD mice. ConclusionsOur study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.

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Mary, A., Barale, S., Eysert, F., Valverde, A., Lacas-Gervais, S., Bauer, C., Eddarkaou, S., Buee, L., Buee-Scherrer, V., Checler, F., Chami, M.. 2024-12-28. Hampered AMPK-ULK1 cascade in Alzheimer disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin. https://doi.org/10.1101/2024.12.28.630598

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