The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer's disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.

中文翻译：

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GABA 能中间神经元对 APP 敲入小鼠模型中淀粉样蛋白-β 斑块病理学的贡献。


β 淀粉样蛋白 (Aβ) 肽是阿尔茨海默病 (AD) 大脑中淀粉样斑块的主要成分，源自淀粉样前体蛋白 (APP) 的连续蛋白水解加工。然而，尚未在体内非过度表达系统中检查不同细胞类型对 Aβ 沉积的贡献。在这里，我们发现内源性 APP 在遍布海马各层的 GABA 能中间神经元的异质亚群中高度表达，表明这些细胞可能对 AD 斑块病理学具有深远的贡献。然后，我们表征了 APP 敲入 AD 小鼠模型海马中淀粉样蛋白负荷的层状分布。为了检查 GABA 能中间神经元对斑块病理学的影响，我们使用细胞类型特异性敲除 BACE1 来特异性阻断这些细胞中 Aβ 的产生。我们发现，在斑块沉积的早期阶段，中间神经元约占海马斑块总负荷的 30%。对斑块负荷的最大贡献 (75%) 发生在 CA1 的锥体层，人类 AD 病例中的斑块最常见，也是锥体细胞体和来自体周靶向中间神经元的突触纽的所在地。这些发现揭示了 GABA 能中间神经元在 AD 病理学中的关键作用。我们的研究还强调了使用 APP 敲入模型来正确评估细胞对淀粉样蛋白负荷的贡献的必要性，因为 APP 过表达转基因模型根据启动子和整合位点而不是根据生理相关的表达机制驱动细胞类型中的表达。