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한양대학교 의과대학

Brain Behav. Immun., Oct 24 2023, S0889-1591(23)00320-3 | https://doi.org/10.1016/j.bbi.2023.10.021 GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model

Hyunhee Park ^a,1, Hyuk Sung Kwon ^a,1, Kyu-Yong Lee^a,1, Ye Eun Kim ^a, Jeong-Woo Son^a, Na-Young Choi ^a, Eun Ji Lee ^a, Myung-Hoon Han ^b, Dong Woo Park^c, Sangjae Kim ^d, Seong-Ho Koh^a,e

^aDepartment of Neurology, Hanyang University Guri Hospital, Hanyang University College of Medicine, 153, Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, South Korea

^bDepartment of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, 153, Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, South Korea

^cDepartment of Radiology, Hanyang University Guri Hospital, Hanyang University College of Medicine, 153, Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, South Korea

^dTeloid Inc., 3580 Wilshire Boulevard, Suite 900-31, Los Angeles, CA 90010, USA

^eDepartment of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul 04763, South Korea

¹Park HH, Kwon HS, and Lee KY contributed equally to this work.

Corresponding authors: Sangjae Kim, Seong-Ho Koh

Abstract

GV1001 protects neural cells from amyloid-β (Aβ) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aβ oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aβ oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-30)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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