缺失 FAM19A5 可减轻 Aβ 斑块负担并改善阿尔茨海默病小鼠模型的认知能力。

IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Experimental Neurobiology Pub Date : 2024-08-31 DOI:10.5607/en24017
Sumi Park, Anu Shahapal, Sangjin Yoo, Hoyun Kwak, Minhyeok Lee, Sang-Myeong Lee, Jong-Ik Hwang, Jae Young Seong
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引用次数: 0

摘要

FAM19A5是一种在大脑中高表达的新型分泌蛋白,可能与阿尔茨海默病(AD)的进展有关。然而,它在阿尔茨海默病发病机制中的作用仍不清楚。在此,我们研究了 FAM19A5 在阿尔茨海默病中的潜在功能。我们培育了部分缺乏FAM19A5的APP/PS1小鼠,称为APP/PS1/FAM19A5+/LacZ小鼠。与对照组APP/PS1小鼠相比,APP/PS1/FAM19A5+/LacZ小鼠的Aβ斑块密度显著降低,并延长了APP/PS1小鼠的寿命。为了进一步探索靶向 FAM19A5 的治疗潜力,我们开发了一种 FAM19A5 抗体。给APP/PS1小鼠注射该抗体后,它们在Y迷宫和被动回避测试中的表现明显改善,表明认知功能增强。这种效果在5XFAD小鼠中得到了复制,5XFAD是一种以Aβ快速积累为特征的早发性AD模型。此外,对5XFAD小鼠进行FAM19A5抗体治疗后,小鼠对新物体的探索能力增强,在新物体识别和Y迷宫测试中的自发交替行为增加,这表明小鼠的认知功能得到了改善。这些研究结果表明,FAM19A5在AD病理学中起着重要作用,用FAM19A5抗体靶向治疗AD可能是一种很有前景的治疗策略。
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FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer's Disease.

FAM19A5, a novel secretory protein highly expressed in the brain, is potentially associated with the progression of Alzheimer's disease (AD). However, its role in the AD pathogenesis remains unclear. Here, we investigated the potential function of FAM19A5 in the context of AD. We generated APP/PS1 mice with partial FAM19A5 deficiency, termed APP/PS1/FAM19A5+/LacZ mice. Compared with control APP/PS1 mice, APP/PS1/FAM19A5+/LacZ mice exhibited significantly lower Aβ plaque density and prolonged the lifespan of the APP/PS1 mice. To further explore the therapeutic potential of targeting FAM19A5, we developed a FAM19A5 antibody. Administration of this antibody to APP/PS1 mice significantly improved their performance in the Y-maze and passive avoidance tests, indicating enhanced cognitive function. This effect was replicated in 5XFAD mice, a model of early-onset AD characterized by rapid Aβ accumulation. Additionally, FAM19A5 antibody treatment in 5XFAD mice led to enhanced exploration of novel objects and increased spontaneous alternation behavior in the novel object recognition and Y-maze tests, respectively, indicating improved cognitive function. These findings suggest that FAM19A5 plays a significant role in AD pathology and that targeting with FAM19A5 antibodies may be a promising therapeutic strategy for AD.

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来源期刊
Experimental Neurobiology
Experimental Neurobiology Neuroscience-Cellular and Molecular Neuroscience
CiteScore
4.30
自引率
4.20%
发文量
29
期刊介绍: Experimental Neurobiology is an international forum for interdisciplinary investigations of the nervous system. The journal aims to publish papers that present novel observations in all fields of neuroscience, encompassing cellular & molecular neuroscience, development/differentiation/plasticity, neurobiology of disease, systems/cognitive/behavioral neuroscience, drug development & industrial application, brain-machine interface, methodologies/tools, and clinical neuroscience. It should be of interest to a broad scientific audience working on the biochemical, molecular biological, cell biological, pharmacological, physiological, psychophysical, clinical, anatomical, cognitive, and biotechnological aspects of neuroscience. The journal publishes both original research articles and review articles. Experimental Neurobiology is an open access, peer-reviewed online journal. The journal is published jointly by The Korean Society for Brain and Neural Sciences & The Korean Society for Neurodegenerative Disease.
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