Aims

Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) are etiological triggers of Alzheimer’s disease (AD) pathology[1]. Altered mitochondrial homeostasis is also considered as an early event in AD development. Strikingly, we and others demonstrated the localization of APP-derived fragments in mitochondria-associated membranes[2]. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established.

Methods

We used human neuroblastoma SH-SY5Y cells expressing the familial APPswe mutation or C99 fragment. We studied 2xTgAD, 3xTgAD mice and adeno-associated-virus (AAV)-C99 injected mice[3]. To discriminate between APP-CTFs and Abeta, we modulated pharmacologically secretases activity. Finally, we analyzed human post-mortem sporadic AD brains.

Results

We demonstrated in cells, that APP-CTFs fragments induce mitochondrial fragmentation, cristae disorganization, mitochondrial hyperpolarization, and a higher production of mitochondrial ROS, independently of Abeta. Moreover, APP-CTFs trigger mitophagic failure characterized by the activation and accumulation of autophagic markers and mitochondrial proteins. We confirmed the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo. Importantly, we showed that APP-CTFs accumulation correlates with mitophagy failure in AD brains[4].

Conclusions

This study unravels the toxicity of APP-CTFs, independently of Abeta, towards mitochondria dysfunctions and mitophagy in AD. Potential pharmacological approaches should focus on mitophagy activation to force the elimination and/or renewal of harmful mitochondria.

[1] Lauritzen I, et al. Acta Neuropathol 2016.

[2] Del Prete D. et al. J Alzheimers Dis 2017.

[3] Bourgeois A, et al. Neurobiol Aging 2018.

[4] Vaillant-Beuchot L.^#, Mary A.^# (co-authors), Acta Neuropathol 2020, under revision.