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Regional differences in Alzheimer's disease pathology confound behavioural rescue after amyloid-β attenuation.
Brain ( IF 10.6 ) Pub Date : 2020-01-01 , DOI: 10.1093/brain/awz371
Christopher D Morrone 1, 2 , Paolo Bazzigaluppi 3 , Tina L Beckett 1 , Mary E Hill 1 , Margaret M Koletar 3 , Bojana Stefanovic 3, 4 , JoAnne McLaurin 1, 2
Affiliation  

Failure of Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

中文翻译:

淀粉样蛋白-β衰减后,阿尔茨海默氏病病理学的区域差异混淆了行为抢救。

阿尔茨海默氏病临床试验未能改善或稳定认知,导致人们需要更好地了解活动性疾病过程中认知能力下降背后的驱动力。为了剖析个体病理学对认知功能的贡献,我们使用了TgF344-AD大鼠模型,该模型概括了在患者人群中观察到的阿尔茨海默氏病病理学的显着特征(淀粉样蛋白,tau内含物,坦率的神经元丢失和认知缺陷)。scyllo-肌醇处理可减轻患有疾病的TgF344-AD大鼠的淀粉样蛋白β肽,在Barnes迷宫的逆向学习阶段中,在新颖的目标识别任务和执行功能中挽救了模式分离。有趣的是,减少淀粉样蛋白-β肽并不能挽救在挖洞任务中的日常生活活动或在Barnes迷宫中的空间记忆。为了了解导致行为抢救的病理相关性,我们研究了海马的神经病理学和体内电生理学特征。通过改善θ和γ谱带之间的跨频耦合,淀粉样蛋白-β肽的衰减减少了海马tau病理,并挽救了成年海马神经发生和神经元功能。为了研究空间记忆缺陷持续存在的机制,我们接下来检查了内嗅皮层的神经病理学,该区域的空间记忆需要向海马输入。内嗅皮质中淀粉样蛋白-β肽的减少对内啡肽tau病理学或内啡肽-海马神经元网络功能障碍没有影响,这是通过对内啡肽刺激的海马反应障碍来衡量的。因此,能否恢复认知功能取决于β-淀粉样蛋白,tau蛋白和神经元网络功能障碍的区域差异,这表明在参加临床试验之前对患者进行分期疾病很重要。这些结果进一步强调了跨疾病进展的组合治疗方法的需要。证明了参加临床试验之前对患者进行分期疾病的重要性。这些结果进一步强调了跨疾病进展的组合治疗方法的需要。证明了参加临床试验之前对患者进行分期疾病的重要性。这些结果进一步强调了跨疾病进展的组合治疗方法的需要。
更新日期:2019-12-31
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