Aims

Mitochondria structure and function alterations are major features of AD (1). The AMP-activated protein kinase (AMPK) promotes mitochondrial health, and multiple AMPK targets are involved in various aspects of mitochondrial homeostasis, mitophagy, and inflammatory response. We investigate the impact of AMPK signaling cascade on mitochondrial dysfunctions, mitophagy and neuroinflammation in AD.

Methods

We used SH-SY5Y cells overexpressing the AD Swedish mutation (APPswe), which accumulate Aβ and APP C-terminal fragments (APP-CTFs), ex vivo in hippocampal organotypic slices transduced with APPswe lentiviruses, and in 3xTgAD mice. We studied mitochondrial functions and mitophagy using biochemical, and imagery approaches. We analyzed neuroinflammation in mice using immunohistochemistry, RT-qPCR, and flux cytometry analyses. APP processing was modulated using γ-secretase inhibitor, or harboring the APPswe expression. We used pharmacological and genetic tools to modulate AMPK expression and activity.

Results

Cells expressing APPswe display a repressed AMPK cascade. Inversely, γ-secretase-mediated blockade of Aβ production and accumulation of APP-CTFs enhance AMPK activity, mitochondrial dysfunctions, and trigger mitophagy blockade. Interestingly, repressing AMPK cascade amplify APP-CTFs accumulation, impair mitochondrial functions, activate mitophagy and trigger dendrite shape alterations. Interestingly, activation of AMPK shows beneficial effects by increasing the number of mature dendritic spines and rescue the learning capacity of 3xTgAD mice. Studies investigating the impact of AMPK modulation on neuroinflammation in 3xTgAD mice are ongoing.

Conclusions

Our data highlight a pathogenic role of AMPK cascade repression in AD and question the potential of AMPK stimulation as a novel track for AD therapy.

(1) Vaillant-Beuchot, L^#., Mary, A^#. et al. ^#Co authors. Acta Neuropathologica (under revision).