Ube2c-inhibition alleviated amyloid pathology and memory deficits in APP/PS1 mice model of AD

Autophagy is a major intracellular degradation pathway for the clearance of damaged organelles and misfolded peptides. Previous studies have indicated that autophagy is involved in the pathogenesis of neurodegenerative disease including Alzheimer’s disease (AD). Defective autophagy and highly expressed ubiquitin-conjugating enzyme 2 C (Ube2c) have been found in AD patients and mouse. However, little is known about the regulation of autophagy in AD. The association of Ube2c with autophagy, amyloid pathology and cognitive deficits in AD remains unclear. In the present study, we characterized over expression of Ube2c and declined autophagy in amyloid β (Aβ)-treated microglia and demonstrated the protective effects of agomelatine (AGO) in APP/PS1 mice. We found that knockdown of Ube2c with AAV2 encoding shUbe2c resulted in an obvious enhancement of autophagy in BV2 microglia cells, and an alleviation of Aβ pathology and memory deficits in APP/PS1 mice. Further, pharmacological inhibition of Ube2c by AGO significantly reduced Aβ plaques, improved synaptic plasticity and cognitive behaviors in APP/PS1 mice, as well as promoted autophagy in microglia. Our findings uncover a potent role of Ube2c over-expression and autophagy decline in the pathogenesis of AD, and suggest that regulation of Ube2c and autophagy may provide an important clue and a potential target for the novel therapeutics of AD. • AD patients and mouse model APP/PS1 present Ube2c upregulation in cortex and hippocampus. • Ube2c downregulation enhances autophagy to promote Aβ clearance in microglia. • Agomelatine inhibited the expression of Ube2c via antagonizing 5-HT 2 C receptor. • Pharmacological or genetic Ube2c knockdown reduces Aβ plaque load and rescues memory impairment in APP/PS1 mice.