Aims

Altered mitochondrial homeostasis occurs early in Alzheimer’s disease (AD) and has been consistently linked to Amyloid beta (Aβ). We investigated the contribution of the amyloid precursor protein C-terminal fragments (APP-CTFs) to mitochondrial defects and examined the therapeutic potential of the AMP-activated protein kinase (AMPK) signaling cascade.

Methods

We studied mitochondria structure, function and mitophagy in cells and mice models mimicking familial forms of AD (FAD). We investigated the contribution of APP-CTFs by modulating β- and γ-secretases activities, expressing APP-CTFs in cells and mice, using a transgenic mouse model accumulating APP-CTFs in the absence of Aβ, and by validating our data in human sporadic AD (SAD) samples. We pharmacologically and genetically modulated AMPK in AD models.

Results

We demonstrated the localization and the accumulation of APP-CTFs in mitochondria of both FAD models and SAD samples [1-3]. We reported that APP-CTFs accumulation triggers, independently from Aβ, mitochondrial structure and function alterations and leads to mitophagic failure phenotype [3]. We reported a repressed AMPK cascade in AD and showed that this contributes to APP-CTFs accumulation, mitochondrial dysfunction and mitophagy. Inversely, activation of AMPK cascade showed several beneficial effects including mitochondria structure, dendritic spines maturation, learning capacity and neuroinflammation.

Conclusions

We unravelled the toxicity of APP-CTFs towards mitochondria, and highlighted a pathogenic role of AMPK cascade repression in AD. Our data pointed-out AMPK cascade as a potential AD therapeutic approach.

1.Del Prete, D., et al. J Alzheimers Dis, 2017.

2.Eysert, F., et al. Int J Mol Sci, 2020.

3.Vaillant-Beuchot, L., et al. Acta Neuropathol, 2021.