Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer...

Rationale: Impairment of autophagy maturation has been implicated in Alzheimer's disease (AD) pathogenesis. However, the mechanism for this impairment has not been elucidated, and whether enhancing autophagy maturation is a viable therapeutic strategy for AD has not been verified. Methods: We examined the autophagosome maturation process in AD cell and mouse models by immunoblotting. To further understand the changes in autophagy in AD brains, we analyzed the transcriptome by RNA-sequencing and measured the expression of RAB7, CCZ1 and MON1A. We performed brain stereotaxic injections of AAV into 3xTg AD mouse brain and WT mouse brain to over-express MON1A/CCZ1 or knockdown MON1A. For in vitro studies, we purified autophagosomes, and determined GTP-RAB7 level in autophagosome fractions by GST-R7BD affinity-isolation assay. Results: We report that the active form of RAB7 was selectively decreased in autophagosome fractions isolated from cells and tissues of AD models, and that this decrease was accompanied by impaired activity of its guanine nucleotide exchange factor (GFE) CCZ1-MON1A. Overexpressing CCZ1-MON1A increased the active form of RAB7, enhanced autophagosome maturation, and promoted degradation of APP-CTFs, Aβ and P-tau in an autophagy-dependent manner in cells and a mouse AD model. Conclusions: Our data reveals that CCZ1-MON1A-RAB7 complex dysfunction is a potential mechanism for autophagosome maturation defects in AD, and advances the possibility that enhancing autophagosome maturation is a novel therapeutic strategy against AD.