Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [5xFAD_snRNAseq]. Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [5xFAD_snRNAseq]

Loss-of-function variants of the ABCA7 gene are associated with the increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. Using neuron-specific Abca7 knockout mice (nAbca7−/−) with or without 5×FAD amyloid model background and postmortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics. Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7−/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7−/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which are further supported by results from human AD brains. Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology. Overall design: Using neuron-specific Abca7 knockout mice (nAbca7−/−) with or without 5×FAD amyloid model background and postmortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics.

ABCA7基因的功能丧失型变异与阿尔茨海默病（Alzheimer's disease, AD）发病风险升高显著相关。目前学界尚未明确神经元ABCA7如何参与阿尔茨海默病的发病机制。
本研究借助携带或不携带5×FAD淀粉样蛋白模型背景的神经元特异性Abca7敲除小鼠（nAbca7−/−）以及阿尔茨海默病死后脑组织样本，通过转录组学（transcriptomics）、脂质组学（lipidomics）等综合组学分析手段，对AD相关表型展开系统性研究。脂质组学分析结果显示，相较于对照组，5×FAD;nAbca7−/−小鼠的脑组织及突触小体（synaptosomes）中脂质谱出现显著异常改变。转录组学分析揭示，神经元ABCA7缺失会改变与线粒体稳态（mitochondrial homeostasis）及细胞凋亡（apoptosis）相关的基因表达与通路富集情况，该调控效应在兴奋性神经元（excitatory neurons）中尤为突出。一致性研究结果表明，从5×FAD;nAbca7−/−小鼠中分离得到的突触小体存在线粒体呼吸功能受损及突触蛋白水平降低的表型，这一发现在人类AD死后脑组织样本中得到进一步验证。
本研究结果证实，在AD病理背景下，神经元ABCA7在维持线粒体稳态过程中发挥关键作用，而线粒体稳态是维持神经元功能与存活的重要基础。
整体实验设计：本研究利用携带或不携带5×FAD淀粉样蛋白模型背景的神经元特异性Abca7敲除小鼠（nAbca7−/−）以及阿尔茨海默病死后脑组织样本，通过转录组学、脂质组学等综合分析手段，对AD相关表型展开研究。