Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model
Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model
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DOI：
10.1038/s41598-020-71767-4
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发表时间：
2020-09-08
影响因子：
4.6
通讯作者：
Gutierrez, Antonia
中科院分区：
文献类型：
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作者：
Fernandez-Valenzuela, Juan Jose;Sanchez-Varo, Raquel;Gutierrez, Antonia
在阿尔茨海默病 (AD) 和其他 tau蛋白病中，微管不稳定会损害轴突和突触的完整性，从而导致神经变性。这些疾病的特征是细胞内过度磷酸化 tau 蛋白的积累，导致神经原纤维病理学。 AD 大脑也会积累淀粉样蛋白 (A beta) 沉积物。然而，迄今为止尚未评估微管稳定剂对 Aβ 病理学的影响。在这里，我们评估了脑渗透性微管稳定剂埃坡霉素 D (EpoD) 在 AD 淀粉样蛋白形成模型中的影响。三个月大的 APP/PS1 小鼠在病理发生前每周注射 EpoD，持续 3 个月。接受治疗的小鼠表现出磷酸 tau 水平显着降低，更有趣的是，细胞内和细胞外海马 Aβ 积累（包括可溶性寡聚形式）也显着降低。此外，还发现显着的认知改善以及突触和神经炎病理的改善。值得注意的是，EpoD 对 SOM 中间神经元（一种高度 AD 易受影响的 GABA 能亚群）发挥神经保护作用。因此，我们的结果表明，EpoD 在类似 AD 的情况下改善了微管动力学和轴突运输，降低了 tau 和 Aβ 水平并促进神经元和认知保护。这些结果强调了细胞骨架病理学和两种主要 AD 蛋白损伤之间存在串扰。因此，微管稳定剂可被视为减缓 tau 蛋白和 Aβ 病理进展的治疗剂。
In Alzheimer's disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (A beta) deposits. However, the effect of microtubule stabilizing agents on A beta pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal A beta accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and A beta levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and A beta pathology.