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.
Highlights
Neurons, as post-mitotic and high-energy demanding cells, are especially sensitive to impairment of mitochondria functions and defective quality control processes
We analyzed mitochondrial structure and function in the neuroblastoma cells expressing the Swedish familial double mutations (APPKM670/671NL: SH-SY5Y APPswe). These cells exacerbate the production of amyloid precursor protein (APP)-CTFs (C99 and C83 derived from the cleavage of APP by β and α secretases, respectively), and amyloid beta (Aβ) peptides [59]
We showed that APPswe cells displayed larger mitochondria
Summary
As post-mitotic and high-energy demanding cells, are especially sensitive to impairment of mitochondria functions and defective quality control processes. Mitochondria provide most of the cell energetic demands by generating ATP, the product of the oxidative phosphorylation (OXPHOS). Along with cell life control, mitochondria are implicated in harmful reactive oxygen species (ROS) production and apoptotic cell death [57]. Acta Neuropathologica (2021) 141:39–65 clearance by mitophagy, the selective degradation process of defective or functionally altered mitochondria [64]. Unhealthy mitochondria with a loss of membrane potential (ΔΨm) stabilize PINK1 at the outer mitochondrial membrane. PINK1 recruits the E3 Ubiquitin ligase Parkin to generate polyubiquitinated proteins recognized by mitophagy adapters (i.e., p62/SQSTM1). Flagged mitochondria are recruited by lipid-bound microtubuleassociated protein 1A/1B-light chain 3 (LC3-II) present on the double-membrane called pre-autophagosome structure. Perturbations of mitochondria physiology are considered hallmarks of several neurodegenerative disorders [28], including Alzheimer’s disease (AD) [34]
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