Kim Han-Byul, Yoo Sangjin, Kwak Hoyun, Ma Shi-Xun, Kim Ryunhee, Lee Minhyeok, Ha Nui, Pyo Soonil, Kwon Soon-Gu, Cho Eun-Ho, Lee Sang-Myeong, Jang Juwon, Kim Won Kyum, Park Hae-Chul, Baek Minkyung, Park Yosub, Park Ji-Young, Park Jin-Woo, Hwang Sun Wook, Hwang Jong-Ik, Seong Jae Young
Neuracle Science Co., Ltd, Seoul, 02841, Republic of Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
Alzheimers Res Ther. 2025 Jul 21;17(1):168. doi: 10.1186/s13195-025-01813-8.
FAM19A5 is a secretory protein primarily expressed in neurons. Although its role in synaptic function has been suggested, the precise molecular mechanisms underlying its effects at the synapse remain unclear. Given that synaptic loss is a critical hallmark of Alzheimer's disease (AD), elucidating the mechanisms involving FAM19A5 could provide valuable insights into reversing synaptic loss in AD.
The binding partner of FAM19A5 was identified through co-immunoprecipitation experiments of mouse brain tissue. The effect of FAM19A5 on spine density in hippocampal neurons was evaluated using immunocytochemistry by overexpressing FAM19A5, treating neurons with FAM19A5 protein, and/or an anti-FAM19A5 antibody NS101. Target engagement of NS101 was determined by measuring FAM19A5 levels in mouse, rat, and human plasma at specific time points post NS101 injection using ELISA. Changes in spine density and dynamics in P301S tauopathy mice were assessed via Golgi staining and two-photon microscopy after NS101 administration. The synaptic strengthening of hippocampal neurons in APP/PS1 amyloidopathy mice after NS101 treatment was assessed by measuring miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs). Cognitive performance in AD mice after NS101 treatment was measured using the Y-maze and Morris water maze tests.
FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to reductions in spine density in mouse hippocampal neurons. Inhibiting FAM19A5 function with NS101 increased spine density. Intravenous administration of NS101 increased spine density in the prefrontal cortex of P301S mice, which initially showed reduced spine density compared to wild-type (WT) mice. NS101 normalized the spine elimination rate in P301S mice, restoring the net spine count to levels comparable to WT mice. NS101 treatment enhanced the frequency of mEPSCs and fEPSPs in the hippocampal synapses of APP/PS1 mice, leading to improved cognitive function. The increases in plasma FAM19A5 levels upon systemic NS101 administration suggest that the antibody effectively engages its target and facilitates the transport of FAM19A5 from the brain.
This study demonstrated that inhibiting FAM19A5 function with an anti-FAM19A5 antibody restores synaptic integrity and enhances cognitive function in AD, suggesting a novel therapeutic strategy for AD.
https://clinicaltrials.gov/study/NCT05143463 , Identifier: NCT05143463, Release date: 3 December 2021.
FAM19A5是一种主要在神经元中表达的分泌蛋白。尽管已经有人提出其在突触功能中的作用，但其在突触处发挥作用的精确分子机制仍不清楚。鉴于突触丧失是阿尔茨海默病（AD）的一个关键标志，阐明涉及FAM19A5的机制可能为逆转AD中的突触丧失提供有价值的见解。
通过对小鼠脑组织进行免疫共沉淀实验来鉴定FAM19A5的结合伴侣。通过过表达FAM19A5、用FAM19A5蛋白和/或抗FAM19A5抗体NS101处理神经元，利用免疫细胞化学评估FAM19A5对海马神经元棘突密度的影响。通过酶联免疫吸附测定法（ELISA）在NS101注射后的特定时间点测量小鼠、大鼠和人类血浆中的FAM19A5水平，以确定NS101的靶点结合情况。在给予NS101后，通过高尔基染色和双光子显微镜评估P301S tau蛋白病小鼠的棘突密度和动态变化。通过测量微小兴奋性突触后电流（mEPSCs）和场兴奋性突触后电位（fEPSPs）来评估NS101处理后APP/PS1淀粉样蛋白病小鼠海马神经元的突触增强情况。使用Y迷宫和莫里斯水迷宫试验测量NS101处理后AD小鼠的认知能力。
FAM19A5与一种突触后粘附分子LRRC4B结合，导致小鼠海马神经元的棘突密度降低。用NS101抑制FAM19A5功能可增加棘突密度。静脉注射NS101可增加P301S小鼠前额叶皮质的棘突密度，与野生型（WT）小鼠相比，P301S小鼠最初的棘突密度较低。NS101使P301S小鼠的棘突消除率恢复正常，使净棘突数量恢复到与WT小鼠相当的水平。NS101处理提高了APP/PS1小鼠海马突触中mEPSCs和fEPSPs的频率，从而改善了认知功能。全身给予NS101后血浆FAM19A5水平升高，表明该抗体有效地作用于其靶点并促进了FAM19A5从大脑中的转运。
本研究表明，用抗FAM19A5抗体抑制FAM19A5功能可恢复AD中的突触完整性并增强认知功能，提示了一种针对AD的新型治疗策略。
https://clinicaltrials.gov/study/NCT05143463 ，标识符：NCT05143463，发布日期：2021年12月3日。
