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

www.nature.com/emm ARTICLE OPEN A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease Younghwan Lee1,6, Hyeri Nam1,6, Ji-Won Lee1, Yeo Jin Ko2, Eum Ji Kim3, Sehee Ha1, Nan Kim1, Ja Wook Koo ✉ ✉ Sangjae Kim5 and Seong-Woon Yu1 3 , Taekwon Son 4✉ , 1234567890();,: © The Author(s) 2026 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 β degradation. Single-cell RNAsequencing 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 β 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. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01729-9 INTRODUCTION Alzheimer disease (AD) is the most common age-associated neurodegenerative disease pathologically defined by accumulation of aggregated amyloid β (Aβ) and intracellular neurofibrillary tangles1. According to the amyloid hypothesis, overproduction and accumulation of Aβ have key roles in the pathogenesis of AD, which is accompanied by synaptic and neuronal loss and progressive cognitive decline2. In addition, overt microglial activation and neuroinflammation in response to Aβ accumulation contribute to neurodegeneration in AD3. Several genome-wide association analyses have brought microglia into the center of attention by revealing that many genetic variants increasing risk of AD are primarily expressed in microglia4–6. Microglia are principal immune cells resident in the central nervous system and are able to phagocytose Aβ and lower Aβ burden7. Also, microglia engagement with Aβ deposits and formation of the microglial barrier can serve protective roles by compacting Aβ plaques and limiting the propagation of Aβ accumulation8. Therefore, microglia response may be protective against the onset of AD. However, pro-inflammatory activation suppresses microglial phagocytosis of Aβ, impairing Aβ clearance9. In response to Aβ accumulation, microglia progressively acquire pro-inflammatory phenotypes and overproduce neurotoxic inflammatory mediators, exacerbating neurodegeneration10,11. Therefore, microglia activation can yield both beneficial and detrimental outcomes. These complex roles of microglia may be reflected by their wide range of different activation states; recent extensive genomics studies at the single-cell or nucleus level have revealed the heterogeneity of microglia phenotypes and identified various subgroups of activated microglia during neurodegeneration12–14. As altered microglia function and neuroinflammation are critical components of AD pathogenesis, it is imperative to search for novel therapeutic agents that can restore normal microglia function. GV1001 is a peptide composed of 16 amino acids derived from the catalytic subunit of human telomerase reverse transcriptase. The original purpose of developing this peptide was for cancer immunotherapy because most malignant tumors achieve their immortality through upregulation of telomerase15. GV1001 is safe and indeed induces immune responses with anticancer efficacies in diverse solid cancers such as pancreatic cancer, non-small-cell lung cancer, melanoma, and hepatocellular carcinoma16–19. Interestingly, a recent phase II clinical trial of GV1001 showed improved cognition in patients with AD. In patients with moderate-to-severe AD, subcutaneous injection of GV1001 at a dosage of 1.12 mg every week for 4 weeks (4 injections) followed by every 2 weeks until week 1 Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea. 2Department of Physiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 3Emotion, Cognitive & Behavior Research Group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea. 4Korea Brain Bank, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea. 5Teloid Inc., Los Angeles, CA, USA. 6These authors contributed equally: Younghwan Lee, Hyeri Nam. ✉email: ; ; Received: 20 June 2025 Revised: 12 February 2026 Accepted: 4 March 2026 Y. Lee et al. 2 24 (10 injections) significantly reduced the decrease in Severe Impairment Battery score compared with the placebo control group, suggesting the beneficial effect of GV1001 (ref. 20). GV1001 was well tolerated without notable safety concerns during the trial20. Encouraged by these promising results, larger clinical studies of GV1001 for AD are currently in progress: a phase III clinical trial in South Korea (NCT05303701) and a phase II clinical trial in the USA (NCT05189210). These studies suggest that GV1001 could provide a promising treatment strategy for AD. However, the mode of action underlying the therapeutic effects of GV1001 against AD, especially about microglia profile, is not well known yet. Here, we report the disease-modifying mechanism of GV1001 in the 5xFAD amyloidogenic mouse model. GV1001 reduced amyloid burden by increasing microglia migration toward the large Aβ plaques and promoting Aβ clearance. By combining virtual target screening and docking simulation with peptide pulldown assay, we found that GV1001 bound to bradykinin receptor 1 (B1R). Further study revealed that binding of GV1001 to B1R activated mammalian target of rapamycin complex 2 (mTORC2)-dependent signaling in microglia, suggesting that rescue of neurodegeneration by GV1001 is mainly via microglial B1R–mTORC2 axis. Additionally, our single-cell RNA-sequencing (scRNA-seq) reinforced these findings and found that GV1001 modulated microglial neurodegenerative phenotype. GV1001 treatment. Cytochalasin D was co-administrated for past 2 h during GV1001 treatment. For in vivo study, R715 was intranasally injected to a final concentration of 0.5 mg/kg, five times a week for 8 weeks. Generation of Aβ1-42 fibrils (fAβ1-42) and Aβ uptake assay Monomeric fluorescein isothiocyanate (FITC)-Aβ1-42 (Bachem) and TAMRA-Aβ1-42 (AnaSpec) were dissolved in dimethyl sulfoxide to a stock (...truncated)