Frazier Hilaree N, Braun David J, Bailey Caleb S, Coleman Meggie J, Davis Verda A, Dundon Stephen R, McLouth Christopher J, Muzyk Hana C, Powell David K, Rogers Colin B, Roy Saktimayee M, Van Eldik Linda J
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA.
Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA.
Brain Behav Immun Health. 2024 Jul 23;40:100826. doi: 10.1016/j.bbih.2024.100826. eCollection 2024 Oct.
Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in "pure" models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies.
An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses.
MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured.
This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies ( anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting.
在临床前试验中，抑制p38α丝裂原活化蛋白激酶（p38α）已显示出作为阿尔茨海默病（AD）治疗方法的巨大前景。然而，先前的临床前研究是在AD病理学的“纯”模型中进行的。绝大多数AD患者患有导致痴呆的合并症，特别是某种形式的血管损伤。因此，本研究旨在测试p38α抑制在合并淀粉样蛋白和血管病变的情况下解决功能障碍的潜力。
将一种淀粉样蛋白过表达小鼠品系（5xFAD）置于为期8周的饮食中，以诱导小血管疾病的高同型半胱氨酸血症（HHcy）模型。在HHcy饮食期间，用可穿透大脑的小分子p38α抑制剂MW150治疗小鼠，随后进行行为、神经影像学、电生理或生化/免疫组织化学分析。
MW150成功减轻了莫里斯水迷宫中的行为损伤，这与突触损失的减轻、tau蛋白磷酸化的减少以及电生理参数的部分正常化相对应。未观察到MW150对所测量的淀粉样蛋白、血管或神经炎症终点有影响。
本研究提供了原理证明，即即使在对认知障碍有混合病理贡献的情况下，抑制p38α也能带来益处。有趣的是，这种益处主要是通过挽救神经元功能介导的，而对主要病理没有任何直接影响。这些数据表明p38抑制剂在各种情况下，特别是在AD中，单独或作为其他AD疗法（抗淀粉样蛋白方法）的辅助手段，在保护认知方面有潜在用途。未来旨在确定与这种益处相关的精确神经元通路的研究可能有助于确定其他适合这种方法的特定合并症，或提示未来在药物靶向方面的改进。
