A selective degeneration of cholinergic neurons mediated by NRADD in an Alzheimer's disease mouse model.
A selective degeneration of cholinergic neurons mediated by NRADD in an Alzheimer's disease mouse model.
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阿尔茨海默病小鼠模型中 NRADD 介导的胆碱能神经元选择性变性
DOI：
10.1016/j.cellin.2022.100060
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发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Li, Xinyan
中科院分区：
文献类型：
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作者：
Li, Lanfang;Zhang, Bing;Tang, Xiaomei;Yu, Quntao;He, Aodi;Lu, Youming;Li, Xinyan
基底前脑中的胆碱能神经元构成前脑胆碱能输入的主要来源，调节包括感觉处理、记忆和注意力在内的多种功能，并且易患阿尔茨海默病（AD）。最近，我们将胆碱能神经元分为两个不同的亚群：钙结合蛋白D28K表达（D28K+）和D28K缺乏（D28K−）神经元。然而，这两个胆碱能亚群中的哪一个在AD中选择性退化以及这种选择性退化的分子机制仍然未知。在这里，我们报告了一个发现，D28K+神经元选择性变性，这种变性诱导焦虑样行为在AD的早期阶段。NRADD的神经元类型特异性缺失有效地挽救了D28K+神经元变性，而外源性NRADD的遗传引入导致D28K−神经元丢失。这项功能获得和丧失的研究揭示了AD疾病进展中胆碱能神经元的亚型特异性变性，因此保证了AD治疗的新分子靶点。AD早期D28K+胆碱能神经元选择性变性。D28K+神经元中NRADD的缺失可防止神经变性。外源性NRADD在D28K−神经元中的表达导致神经变性。
Cholinergic neurons in the basal forebrain constitute a major source of cholinergic inputs to the forebrain, modulate diverse functions including sensory processing, memory and attention, and are vulnerable to Alzheimer's disease (AD). Recently, we classified cholinergic neurons into two distinct subpopulations; calbindin D28K-expressing (D28K+) versus D28K-lacking (D28K−) neurons. Yet, which of these two cholinergic subpopulations are selectively degenerated in AD and the molecular mechanisms underlying this selective degeneration remain unknown. Here, we reported a discovery that D28K+ neurons are selectively degenerated and this degeneration induces anxiety-like behaviors in the early stage of AD. Neuronal type specific deletion of NRADD effectively rescues D28K+ neuronal degeneration, whereas genetic introduction of exogenous NRADD causes D28K− neuronal loss. This gain- and loss-of-function study reveals a subtype specific degeneration of cholinergic neurons in the disease progression of AD and hence warrants a novel molecular target for AD therapy. D28K+ cholinergic neurons are selectively degenerated in the early stage of AD. Deletion of NRADD in D28K+ neurons protects against neurodegeneration. Expression of exogenous NRADD in D28K− neurons causes neurodegeneration.