Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

Abstract

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 β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ 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 γ-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 Aβ 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.

Microbiome-Metabolomics Reveals Endogenous Alterations of Energy Metabolism by the Dushen Tang to Attenuate D-Galactose-Induced Memory Impairment in Rats

“…Mitochondrial dysfunction and a decline in respiratory chain function alter amyloid precursor protein processing, which leads to the production of pathogenic amyloid-β fragments [30][31][32]. Mitochondrial disorders are one of the main pathogenic factors of AD, and the size and shape of the mitochondria and organelles return to normal after DST treatment, which suggests the protective effect of DST [33,34]. Lactic acid accumulation was observed in the model group with memory impairment, and this accumulation might have been observed due to decreased pyruvate dehydrogenase activity, which results in decreased catabolism of lactic acid and reduced mitochondrial respiration and thereby mitochondrial failure.…”

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

“…In animals displaying rodent APP, the protein was found to be mainly processed by α-secretase, thus generating almost only C83, whereas the presence of human APP increases β-secretase cleavage and leads to enhanced C99 levels (134). These data thus reveal a different APP processing of human and rodent APP, which could explain the higher levels of C99 in human as compared with rodents (137) and may be one of the reasons for the C99 accumulation observed even in SAD cases (126,137,138). Overall, these findings ruled out the possibility that it could be "model specific" but rather suggest that it should be a common and early alteration in AD.…”

Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer’s Disease

“…Because the secretases have different distribution within the cells, the itinerary followed by the APP is crucial for determining the amount of APP fragments. Furthermore, CTFs have been found localized to subcellular microdomains between the ER and mitochondria [ 47 ], and they can lead, as well as Aβ, to mitochondrial dysfunction and morphology alteration in in vivo and in vitro AD study models [ 48 , 49 , 50 ]. According to findings in the literature, we observed an altered mitochondrial network in fAD cells.…”