Karaahmet Berke, Olschowka John A, O'Banion M Kerry
Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY 14642, USA.
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Pharmaceutics. 2023 Jun 24;15(7):1809. doi: 10.3390/pharmaceutics15071809.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that involves strong inflammatory components. Aberrant and prolonged inflammation in the CNS is thought to contribute to the development of the pathology. The use of single cytokine approaches to curb or leverage inflammatory mechanisms for disease modifying benefit has often resulted in conflicting data. Furthermore, these treatments were usually delivered locally into the CNS parenchyma, complicating translational efforts. To overcome these hurdles, we tested the use of glatiramer acetate (GA) in reducing amyloid beta (Aβ) plaque pathology in the 5xFAD model of AD. GA immunizations were begun at the ages of 2.5 months, 5.5 months, and 8.5 months, and GA was delivered weekly for 8 weeks. While previous data describe potential benefits of GA immunization in decreasing Aβ levels in murine models of AD, we found modest decreases in Aβ levels if given during the development of pathology but, surprisingly, found increased Aβ levels if GA was administered at later stages. The impact of GA treatment was only significant for female mice. Furthermore, we observed no changes between microglial uptake of plaque, CD11c immunopositivity of microglia, or levels of TMEM119 and P2Ry12 on microglia. Overall, these data warrant exercising caution when aiming to repurpose GA for AD.
阿尔茨海默病（AD）是一种涉及强烈炎症成分的慢性神经退行性疾病。中枢神经系统（CNS）中异常且持续的炎症被认为会促进病理发展。使用单一细胞因子方法来抑制或利用炎症机制以获得疾病修饰益处往往会产生相互矛盾的数据。此外，这些治疗通常是局部递送至CNS实质，这使得转化研究变得复杂。为了克服这些障碍，我们测试了醋酸格拉替雷（GA）在减少AD的5xFAD模型中淀粉样β蛋白（Aβ）斑块病理方面的作用。GA免疫在2.5个月、5.5个月和8.5个月龄开始，每周给药GA，持续8周。虽然先前的数据描述了GA免疫在降低AD小鼠模型中Aβ水平方面的潜在益处，但我们发现，如果在病理发展过程中给予GA，Aβ水平会适度降低，但令人惊讶的是，如果在后期给予GA，Aβ水平会升高。GA治疗的影响仅对雌性小鼠显著。此外，我们观察到小胶质细胞对斑块的摄取、小胶质细胞的CD11c免疫阳性或小胶质细胞上TMEM119和P2Ry12的水平之间没有变化。总体而言，这些数据表明，在旨在将GA重新用于治疗AD时需谨慎行事。
