A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease

초록

GV1001 is a peptide consisting of 16 amino acids derived from the catalytic subunit of human telomerase reverse transcriptase. A recent phase II clinical trial in patients with Alzheimer disease (AD) showed that GV1001 effectively improved memory impairment with proven safety, leading to larger clinical trials. However, the mechanisms underlying therapeutic effects of GV1001 on AD remain elusive. Here, we report that GV1001 reduces amyloid plaque burden and rescues synaptic loss and memory deficits in 5xFAD mice by increasing microglial migration toward large amyloid plaques and amyloid beta degradation. Single-cell RNA-sequencing revealed that GV1001 promoted the migratory and phagocytic phenotypes by modulating disease-associated microglial profiles. At the molecular level, through virtual target screening and docking simulation combined with peptide pulldown, we identified that bradykinin receptor 1 is the binding target of GV1001. Furthermore, we revealed that GV1001 facilitated microglial migration and amyloid beta phagocytosis in an mTORC2-dependent manner. Collectively, our work demonstrates the amyloidolytic effects and the relevant in-depth signaling mechanism of GV1001 in microglia, suggesting GV1001 as a promising disease-modifying therapeutic agent for AD.

키워드