Supplementary Figure 11: Working model.

Upper panel: The roles of mitophagy were evaluated in AD pathology utilizing postmortem human AD brain samples, AD iPSC-derived neurons, and transgenic animal models of AD, including C. elegans and mice. Lower panel: We propose the synergistic roles and relationships between Aβ, p-Tau, and defective mitophagy in AD progression. In the red panel: The underlying cause in most AD cases is complex, likely reflecting risk associated with aging, multiple genetic factors as well as non-genetic (for example, environmental, lifestyle/behavioral and metabolic) factors. These factors can directly/indirectly cause mitophagy defects, leading to accumulation of damaged mitochondria, a major feature in both familial and sporadic AD patients. Defective mitophagy, damaged mitochondria, and Tau tangles/Aβ plaques, exacerbate one another (dashed arrow, further work necessary), causing neurodegeneration and impaired phagocytosis by microglia, and the gradual development of AD pathology in brain. Evidence of Tau/Aβ-induced reduction of mitochondrial motility were from (Ram D. et al., Science 2008; Tammineni P et a., Autophagy 2017). In the blue panel: Mitophagy induction maintains a healthy mitochondrial pool through efficient clearance of dysfunctional organelles. Healthy mitochondria augment neuronal function and survival as well as promote the clearance of extracellular Aβ plaques by microglia. Proficient mitophagy maintains a healthy brain.