Journal
ACTA NEUROPATHOLOGICA
Volume 141, Issue 1, Pages 39-65Publisher
SPRINGER
DOI: 10.1007/s00401-020-02234-7
Keywords
Alzheimer's disease; Amyloid precursor protein; Amyloid beta; APP-CTFs; C99; C83; Mitochondria; Mitophagy
Categories
Funding
- Inserm
- Fondation Vaincre Alzheimer [FR18-035]
- Universite Cote d'Azur (Living-systems-complexity-and-diversity)
- LABEX (excellence laboratory, program investment for the future)
- DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease)
- University Hospital Federation (FHU) OncoAge
- Sao Paulo Research Foundation (FAPESP) [2018/14289-6]
- DISTALZ
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [18/14289-6] Funding Source: FAPESP
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Recent evidence suggests that APP-CTFs may trigger AD pathology, while mitochondrial dysfunction is considered an early event in AD development. Accumulation of APP-CTFs can lead to mitochondrial morphological changes and impaired basal mitophagy, possibly playing a crucial role in AD pathogenesis.
Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer's disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the beta-secretase-derived APP-CTF fragment (C99) combined with beta- and gamma-secretase inhibition, that APP-CTFs accumulation independently of A beta triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with gamma-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of A beta to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.
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