TREM2 deficiency exacerbates cognitive impairment by aggravating α-Synuclein-induced lysosomal dysfunction in Parkinson’s disease

/A53T mice. In addition, transcriptional analyses and in vitro experiments further found that TREM2 knockdown inhibited the nuclear distribution of TFEB via the ERK1/2 pathway, exacerbating α-Syn-induced lysosomal dysfunction and causing more pathological α-Syn accumulation. Finally, HT22 cells were cocultured with TREM2 knockdown of BV-2 cells pretreated with recombinant human A53T α-Syn preformed fibrils (PFFs). The coculture experiments showed that TREM2 knockdown in BV-2 cells pretreated with PFFs enhanced the phosphorylation of α-Syn and promoted apoptosis in HT22 cells via inhibiting α-Syn degradation. In conclusion, TREM2 deficiency exacerbates cognitive impairment in PD by exacerbating α-Syn-induced microglial lysosomal dysfunction, identifying TREM2 as a potential therapeutic target.