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Aggregated tau is a hallmark neuropathological feature in numerous neurodegenerative disorders. Previous studies aiming to validate aggregated tau pathology as a pathogenic driver of neurodegeneration in correlation to characteristic behavioral phenotypes have had shortcomings. Although studies on soluble tau pathology have effectively addressed these shortcomings, the role of soluble tau in the molecular pathogenesis of neurodegeneration is not yet unequivocally established. In sporadic Alzheimer’s disease (AD), the relevance of soluble tau pathology in endolysosomal dysfunction and autophagic stress, some of the earliest disease manifestations, is unclear. In this study, we report that soluble 4R0N tau overexpression affects the expression levels of certain markers associated with the endolysosomal system and autophagy. Moreover, through live-cell imaging, we found that the vesicular dynamics of early endosomes were affected with respect to spatiotemporal parameters and vesicle maturation. Additionally, we observed the localization of amyloid precursor protein (APP) along the endocytic pathway and found that upon overexpression of soluble 4R0N tau, APP was preferentially localized to the endocytic compartments implicated in the amyloidogenic pathway. Overall, our observations indicate that soluble 4R0N tau abrogates the dynamics of the endolysosomal system, autophagy, and affects the trafficking of APP. Since the amyloidogenic processing of APP occurs during its progression through the endocytic pathway, our results suggest that the generation of amyloid-β (Aβ) might also be modulated.

Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria owing to their high bioenergetic demand. Mitochondrial dysfunction is therefore associated with various age-related neurodegenerative disorders such as Alzheimer’s disease (AD), wherein accumulation of damaged and dysfunctional mitochondria has been reported as an early symptom further contributing to disease progression. In AD, impairment of mitochondrial function causes bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby aggravating the effect of Aβ and tau pathologies, leading to synaptic dysfunction, cognitive impairment and memory loss. Although there are reports suggesting intricate parallelism between mitochondrial dysfunction and AD pathologies such as Aβ aggregation and hyperphosphorylated tau accumulation, the factors that drive the pathogenesis of either are unclear. In addition, emerging evidence suggest that mitochondrial quality control (QC) mechanisms such as mitophagy are impaired in AD. As an important mitochondrial QC mechanism, mitophagy plays a critical role in maintaining neuronal health and function. Studies show that various proteins involved in mitophagy, mitochondrial dynamics, and mitochondrial biogenesis are affected in AD. Compromised mitophagy may also be attributed to impairment in autophagosome–lysosome fusion and defects in lysosomal acidification. Therapeutic interventions aiming to restore mitophagy functions can be used as a strategy for ameliorating AD pathogenesis. Recent evidence implicates the role of microglial activation via mitophagy induction in reducing amyloid plaque load. This review summarizes the current developments in the field of mitophagy and mitochondrial dysfunction in AD.