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Tau, synapse loss and gliosis progress in an Alzheimer’s mouse model after amyloid-β immunotherapy
Brain ( IF 10.6 ) Pub Date : 2024-11-06 , DOI: 10.1093/brain/awae345
Lindsay A Welikovitch, Anastasie Mate de Gerando, Anita Khasnavis, Harshil Bhavsar, Jonah C Meltzer, Luc Buée, Lori B Chibnik, Thierry Bussiere, Bradley T Hyman

While preclinical studies assessing drugs for Alzheimer’s disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well-established that amyloid (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict how targeting one might influence the other, as well as downstream degeneration. We developed a transgenic mouse model, APP/PS1xTau22, with progressive cortical Aβ deposition and hippocampal tau neurofibrillary inclusions to investigate how both neuropathologies act jointly to bring about neural degeneration, synapse loss, and glial phenotypes. We then assessed whether applying murine chimeric Aducanumab, an anti-amyloid immunotherapy, could impact the synergistic relationship between amyloid and tau. Drug treatment resulted in a ∼70% reduction in Aβ deposition in hippocampal and cortical areas and produced a robust peri-plaque microglial and astrocytic response. Removing amyloid from the brain did not reverse or slow tau pathology or alter synapse loss. Our findings suggest that, once the interaction between amyloid and tau is set in motion, reducing plaque burden by Aβ immunotherapy may stimulate glial responses, but is insufficient to curb degenerative phenotypes in this model.

中文翻译:


β淀粉样蛋白免疫治疗后阿尔茨海默病小鼠模型的 tau、突触丢失和胶质增生进展



虽然评估阿尔茨海默病 (AD) 药物的临床前研究是在通常只显示 AD 的一种神经病理学特征的动物模型中进行的,但患者表现出合并症和神经病理学的复杂组合。重要的是,众所周知,淀粉样蛋白 (Aβ) 斑块和 tau 缠结积累以相位依赖性方式相互作用,因此很难预测靶向一个可能如何影响另一个以及下游变性。我们开发了一种转基因小鼠模型 APP/PS1xTau22,具有进行性皮质 Aβ 沉积和海马 tau 神经原纤维包涵体,以研究两种神经病理如何共同作用导致神经变性、突触丢失和神经胶质表型。然后,我们评估了应用小鼠嵌合 Aducanumab(一种抗淀粉样蛋白免疫疗法)是否会影响淀粉样蛋白和 tau 之间的协同关系。药物治疗导致海马和皮质区域的 Aβ 沉积减少 ∼70%,并产生强烈的斑块周围小胶质细胞和星形胶质细胞反应。从大脑中去除淀粉样蛋白不会逆转或减缓 tau 病理或改变突触丢失。我们的研究结果表明,一旦淀粉样蛋白和 tau 之间的相互作用开始,通过 Aβ 免疫疗法减少斑块负荷可能会刺激神经胶质反应,但不足以抑制该模型中的退行性表型。
更新日期:2024-11-06
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