Goettemoeller Annie M, Banks Emmie, McCann Katharine E, Kumar Prateek, South Kelly, Olah Viktor J, Ramelow Christina C, Duong Duc M, Seyfried Nicholas T, Rangaraju Srikant, Weinshenker David, Rowan Matthew Jm
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322.
GDBBS Graduate Program, Laney Graduate School, Emory University.
Res Sq. 2023 Nov 6:rs.3.rs-3370607. doi: 10.21203/rs.3.rs-3370607/v1.
Preventative treatment for Alzheimer's Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer's Disease remain unknown. In human patients with Alzheimer's Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer's Disease. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer's. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. Furthermore, the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression, likely resulting from PV-interneuron variability between the two regions based on physiological and proteomic evaluations. Interestingly, entorhinal hAPP-induced hyperexcitability was quelled by co-expression of human Tau at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer's Disease and downstream cognitive decline.
阿尔茨海默病的预防性治疗至关重要，然而，阿尔茨海默病早期区域易损性的细胞机制仍然未知。在患有阿尔茨海默病的人类患者中，最早观察到的与认知衰退相关的病理生理特征之一是兴奋性过高。在小鼠模型中，内嗅皮层已被证明存在早期兴奋性过高，内嗅皮层是受阿尔茨海默病影响的第一个皮层区域。疾病早期兴奋性过高的起源以及为何它优先出现在特定区域尚不清楚。利用皮层区域和细胞类型特异性蛋白质组学以及膜片钳电生理学，我们在散发性阿尔茨海默病模型中发现了对人类特异性淀粉样前体蛋白（hAPP）的不同易感性。出乎意料的是，我们的研究结果表明，早期内嗅兴奋性过高可能是由小白蛋白中间神经元的内在易损性导致的，而不是怀疑的II层兴奋性神经元。内嗅PV中间神经元的这种易损性是hAPP特有的，因为增加小鼠APP表达无法重现这一现象。此外，体感皮层对成年期hAPP表达没有这种易损性，这可能是基于生理学和蛋白质组学评估，两个区域之间PV中间神经元存在差异所致。有趣的是，通过共表达人类Tau蛋白可抑制内嗅hAPP诱导的兴奋性过高，但代价是增加了病理性tau蛋白种类。这项研究表明，针对非兴奋性细胞类型的早期疾病干预措施可能会保护那些对阿尔茨海默病病理症状和下游认知衰退具有早期易损性的区域。
