Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimer's disease.
Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimer's disease.
复制标题
遗传背景控制阿尔茨海默病小鼠模型中的早期小胶质细胞-突触相互作用。
DOI：
10.1101/2023.04.28.538728
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bloss,ErikB
中科院分区：
文献类型：
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作者：
Heuer,SarahE;Keezer,KellyJ;Hewes,AmandaA;Onos,KristenD;Graham,KourtneyC;Howell,GarethR;Bloss,ErikB
阿尔茨海默病（AD）的共同特征包括淀粉样蛋白病理、小胶质细胞激活和突触功能障碍，然而，它们之间的因果关系尚不清楚。此外，人类数据表明，对阿尔茨海默病神经病理学的易感性和恢复力是由遗传环境控制的，这是一个在小鼠模型中未被充分探索的因素。为此，我们利用病毒策略在基因多样化的C57BL/6J （B6）和PWK/PhJ (PWK) APP/PS1小鼠品系中标记ad易感的CA1树突神经元回路，并使用PLX5622非侵入性消耗脑小胶质细胞。对标记神经元的重建显示，B6野生型（WT）和APP/PS1小鼠树突棘密度和形态的变化依赖于小胶质细胞，但PWK小鼠的棘具有明显的稳定性。我们进一步发现突触变化依赖于B6中小胶质细胞-树突的直接相互作用。APP/PS1但不包括PWK。APP / PS1老鼠。总的来说，这些结果表明，在特定的ad易感投射途径中，小胶质细胞依赖的突触改变受到遗传环境的差异控制。
Common features of Alzheimer’s disease (AD) include amyloid pathology, microglia activation and synaptic dysfunction, however, the causal relationships amongst them remains unclear. Further, human data suggest susceptibility and resilience to AD neuropathology is controlled by genetic context, a factor underexplored in mouse models. To this end, we leveraged viral strategies to label an AD-vulnerable neuronal circuit in CA1 dendrites projecting to the frontal cortex in genetically diverse C57BL/6J (B6) and PWK/PhJ (PWK) APP/PS1 mouse strains and used PLX5622 to non-invasively deplete brain microglia. Reconstructions of labeled neurons revealed microglia-dependent changes in dendritic spine density and morphology in B6 wild-type (WT) and APP/PS1 yet a marked stability of spines across PWK mice. We further showed that synaptic changes depend on direct microglia-dendrite interactions in B6.APP/PS1 but not PWK.APP/PS1 mice. Collectively, these results demonstrate that microglia-dependent synaptic alterations in a specific AD-vulnerable projection pathway are differentially controlled by genetic context.