UK Dementia Research Institute at UCL, University College London, London, United Kingdom.
Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, United Kingdom.
PLoS Biol. 2024 Jul 23;22(7):e3002727. doi: 10.1371/journal.pbio.3002727. eCollection 2024 Jul.
Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.
已经证明减少淀粉样蛋白β（Aβ）在治疗阿尔茨海默病（AD）方面是有效的，但神经元是致病 Aβ的主要来源这一基本假设尚未得到验证。在这里，我们通过证明少突胶质细胞是人类大脑中 Aβ的重要来源，并在 AD 基因敲入小鼠模型中发挥关键作用促进异常神经元过度兴奋，从而挑战了这一普遍观点。我们表明，选择性抑制少突胶质细胞 Aβ的产生可改善 AD 大脑病理并恢复体内小鼠模型中的神经元功能。我们的研究结果表明，靶向少突胶质细胞 Aβ的产生可能是治疗 AD 的一种有前途的治疗策略。
