Sertad1 is elevated and plays a necessary role in neuron loss and cognitive impairment in a mouse model of Alzheimer's disease

Aberrant activation of autophagy contributes to neuronal cell death and plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). To study this further, we assessed autophagy-related (ATG) proteins in 5xFAD mice at different ages and found a progressive inappropriate elevation of autophagic proteins in these mice. We identified a transcriptional coregulator, Sertad1 (SERTA domain-containing protein 1), which plays a necessary role in neuron death, as a key regulator of aberrant autophagy in AD. We found a progressive elevation in Sertad1 levels in 5xFAD mice with age compared with WT mice. Sertad1 knockdown in 5xFAD mice brains lowered levels of ATG proteins and lysosomal proteins, suggesting its role in the regulation of the autophagy-lysosomal pathway. We found that Sertad1 knockdown restored Akt activity, which is inhibited in AD, and blocked the activation of its target, FoxO3a, which is translocated to the nucleus in the absence of active Akt and mediates neuron death by apoptosis and autophagy. Furthermore, we showed that lentivirus-mediated RNAi targeting of Sertad1 in 5xFAD mice led to better performance in behavioral experiments compared with 5xFAD mice treated with nontargeting shRNA, accompanied by significant restoration of synaptic integrity. Overall, our results demonstrated that autophagy is robustly induced with disease progression, but ATG proteins accumulate in the brain because of their impaired clearance; Sertad1 knockdown restored synaptic failure and improved cognition in 5xFAD mice by enhancing clearance of ATG proteins and neuronal survival. Hence, Sertad1 could be an excellent target for therapeutic intervention to combat the multifaceted pathologies of AD.