Mitophagy in Alzheimer's disease: Molecular defects and therapeutic approaches

Abstract

Mitochondrial dysfunctions are central players in Alzheimer's disease (AD). In addition, impairments in mitophagy, the process of selective mitochondrial degradation by autophagy leading to a gradual accumulation of defective mitochondria, have also been reported to occur in AD. We provide an updated overview of the recent discoveries and advancements on mitophagic molecular dysfunctions in AD-derived fluids and cells as well as in AD brains. We discuss studies using AD cellular and animal models that have unraveled the contribution of relevant AD-related proteins (Tau, Aβ, APP-derived fragments and APOE) in mitophagy failure. In accordance with the important role of impaired mitophagy in AD, we report on various therapeutic strategies aiming at stimulating mitophagy in AD and we summarize the benefits of these potential therapeutic strategies in human clinical trials.

Fig. 1. Amyloidogenic and non-amyloidogenic processing of APP.

The amyloid precursor protein (APP) is synthesized in the endoplasmic reticulum (ER) and passes through the Golgi apparatus where it undergoes several post-translational modifications such as N- and O-glycosylations, sialylations, phosphorylations and sulfatations before reaching the plasma membrane (PM) in its mature form (mAPP). There, APP can be processed into two different pathways. A In physiological conditions, APP mainly follows the non-amyloidogenic pathway (green arrows), where it is cleaved by the α-secretase, producing secreted sAPPα fragment and membrane-anchored APP-CTF-α (C83), which is then cleaved by the γ-secretase generating secreted P3 fragment and APP intracellular domain (AICD) fragment. Under physiological conditions, APP is also marginally processed in the amyloidogenic pathway (red arrows), in which it is first internalized in endosomes and cleaved by the β-secretase generating sAPPβ fragment and membrane-anchored APP-CTF-β (C99). The latter is subsequently cleaved by the γ-secretase to generate Aβ and AICD (APP intracellular domain), or by the α-secretase to generate the C83 peptide. B In Alzheimer’s disease (AD), APP is mostly processed in the amyloidogenic pathway. It also accumulates and is processed in the intracellular compartments including the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), where secretases are also present. Secreted monomeric Aβ_1-42 (moAβ_1-42) peptide is prone to oligomerize (oAβ_1-42) and generates extracellular amyloid plaques.

Fig. 2. Physiological mitophagy processes and alterations linked to Tau, Aβ, APP-CTFs and APOE.

A Following mitochondrial stress (i.e., mitochondria membrane (ΔΨmit) depolarization, or a general cellular stress (i.e. hypoxia, ischemia, starvation)), mitochondria undergo a specific degradation mechanism by mitophagy. The PINK1/Parkin-dependent mitophagy is driven by a decrease of ∆Ψmit, triggering the stabilization of PTEN-induced putative kinase 1 (PINK1) at the OMM and the recruitment of the E3 Ubiquitin ligase Parkin, generating poly-phospho-ubiquitinated chains (p-S65-Ub) on OMM proteins that act as a “eat-me” signal for damaged mitochondria. Cytosolic proteins that can act as mitophagy receptors (p62, OPTN, NDP52, NBR1, or TAX1BP1) will recognize and bind to p-S65-Ub decorated proteins and will recruit the phagosome through their interaction, via their LIR motif with LC3-II (the activated form of the microtubule-associated protein 1 A/1B light chain 3) present at the surface of the phagosome. Besides, in the PINK1/Parkin-independent mitophagy, the phagosome is recruited around mitochondria directly through LIR motif-containing OMM receptors (NIX/BNIP3L, BNIP3, FUNDC1, BCL2L13, FKBP8, DISC1, AMBRA1, or MCL-1) or through the recognition of cardiolipin (CL) exposed on the OMM. Once the phagophore is recruited, it engulfs damaged mitochondria to generate the mitophagosome. Then, lysosomes can fuse with mitophagosomes to form mitolysosomes and degrade damaged mitochondria by acidic hydrolases. B–E Mitophagic process is perturbed in AD by Tau species (B), Aβ species (C). APP-CTFs (D), and APOE4 isoform and/or high cholesterol levels (E). Proteins that are impacted in the mitophagy process are depicted in grey in (B–E) instead of being colored as in (A). Inhibitory functions are indicated by red arrows, and green arrows indicate PINK1/Parkin activation and phagophore formation or recruitment.