阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，也是痴呆的主要原因，其特征是神经元和突触损失、β 淀粉样蛋白和 tau 蛋白聚集，以及涉及神经炎症、血管功能障碍和代谢紊乱的多因素病理。此外，越来越多的证据表明 AD 大脑中神经元兴奋和抑制之间的不平衡继发于小白蛋白 (PV) 和生长抑素 (SST) 阳性中间神经元的功能障碍，这些中间神经元差异调节神经元活动。重要的是，AD 中神经元活性受损可能发生在淀粉样蛋白-β 病理学的上游，使其成为潜在的治疗靶点。为了确定中间神经元功能障碍所涉及的潜在病理过程，我们对 5XFAD AD 小鼠模型与对照组的大脑转录组进行了空间分析，涉及早期阶段（12 周-成年）和晚期（30周龄）疾病。对差异表达基因 (DEG) 进行全局比较，然后对 5XFAD 与对照进行富集分析，强调了早期疾病中与 RNA 和蛋白质加工、运输和清除相关的各种生物途径以及疾病晚期的神经变性途径。早期 DEG 检查发现共享的（例如 RNA 和蛋白质生物学）和不同的（例如 N-聚糖生物合成）、PV 与生长抑素 SST 阳性中间神经元和兴奋性神经元中丰富的途径，这些神经元表达神经退行性和轴突和突触相关通路。在疾病晚期，PV 阳性中间神经元以癌症和癌症信号传导途径以及神经元和突触途径为特征，而 SST 阳性中间神经元则表现出聚糖生物合成和各种感染途径。晚期兴奋性神经元的主要特征是神经退行性途径。这些 PV 和 SST 阳性中间神经元的细粒度转录组图谱以时间和空间依赖的方式为潜在的 AD 病理生理学和治疗靶点提供了新的见解。

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and leading cause of dementia, characterized by neuronal and synapse loss, amyloid-β and tau protein aggregates, and a multifactorial pathology involving neuroinflammation, vascular dysfunction, and disrupted metabolism. Additionally, there is growing evidence of imbalance between neuronal excitation and inhibition in the AD brain secondary to dysfunction of parvalbumin (PV)- and somatostatin (SST)-positive interneurons, which differentially modulate neuronal activity. Importantly, impaired interneuron activity in AD may occur upstream of amyloid-β pathology rendering it a potential therapeutic target. To determine the underlying pathologic processes involved in interneuron dysfunction, we spatially profiled the brain transcriptome of the 5XFAD AD mouse model versus controls, across four brain regions, dentate gyrus, hippocampal CA1 and CA3, and cortex, at early-stage (12 weeks-of-age) and late-stage (30 weeks-of-age) disease. Global comparison of differentially expressed genes (DEGs) followed by enrichment analysis of 5XFAD versus control highlighted various biological pathways related to RNA and protein processing, transport, and clearance in early-stage disease and neurodegeneration pathways at late-stage disease. Early-stage DEGs examination found shared, e.g ., RNA and protein biology, and distinct, e.g ., N-glycan biosynthesis, pathways enriched in PV-versus somatostatin SST-positive interneurons and in excitatory neurons, which expressed neurodegenerative and axon- and synapse-related pathways. At late-stage disease, PV-positive interneurons featured cancer and cancer signaling pathways along with neuronal and synapse pathways, whereas SST-positive interneurons showcased glycan biosynthesis and various infection pathways. Late-state excitatory neurons were primarily characterized by neurodegenerative pathways. These fine-grained transcriptomic profiles for PV- and SST-positive interneurons in a time- and spatial-dependent manner offer new insight into potential AD pathophysiology and therapeutic targets.