Physiological Sciences Graduate Program, University of Arizona, Tucson, AZ, United States.
Department of Neurology, University of Arizona, Tucson, AZ, United States.
Exp Neurol. 2024 Nov;381:114926. doi: 10.1016/j.expneurol.2024.114926. Epub 2024 Aug 15.
Cognitive decline in Parkinson's Disease (PD) is a prevalent and undertreated aspect of disease. Currently, no therapeutics adequately improve this aspect of disease. It has been previously shown that MAS receptor agonism via the glycosylated Angiotensin (1-7) peptide, PNA5, effectively reduces cognitive decline in models of vascular contributions to cognitive impairment and dementia (VCID). PNA5 has a brain/plasma ratio of 0.255 indicating good brain penetration. The goal of the present study was to determine if (1) systemic administration of PNA5 rescued cognitive decline in a mouse model of PD, and (2) if improvements in cognitive status could be correlated with changes to histopathological or blood plasma-based changes. Mice over-expressing human, wild-type α-synuclein (αSyn) under the Thy1 promoter (Thy1-αSyn mice, "line 61") were used as a model of PD with cognitive decline. Thy1-αSyn mice were treated with a systemic dose of PNA5, or saline (1 mg/kg/day) beginning at 4 months of age and underwent behavioral testing at 6 months, compared to WT. Subsequently, mice brains were analyzed for changes to brain pathology, and blood plasma was examined with a Multiplex Immunoassay for peripheral cytokine changes. Treatment with PNA5 reversed cognitive dysfunction measured by Novel Object Recognition and spontaneous alteration in a Y-maze in Thy1-αSyn mice. PNA5 treatment was specific to cognitive deficits, as fine-motor disturbances were unchanged. Enhanced cognition was associated with decreases in hippocampal inflammation and reductions in circulating levels of Macrophage Induced Protein (MIP-1β). Additionally, neuronal loss was blunted within the CA3 hippocampal region of PNA5-treated αsyn mice. These data reveal that PNA5 treatment reduces cognitive dysfunction in a mouse model of PD. These changes are associated with decreased MIP-1β levels in plasma identifying a candidate biomarker for target engagement. Thus, PNA5 treatment could potentially fill the therapeutic gap for cognitive decline in PD.
帕金森病（PD）的认知能力下降是疾病的一个普遍且未得到充分治疗的方面。目前，尚无治疗方法能充分改善这种疾病。先前的研究表明，通过糖基化血管紧张素（1-7）肽 PNA5 激动 MAS 受体可有效减轻血管性认知损害和痴呆（VCID）模型中的认知能力下降。PNA5 的脑/血浆比为 0.255，表明具有良好的脑穿透性。本研究的目的是确定（1）PNA5 的全身给药是否可以挽救 PD 小鼠模型中的认知能力下降，以及（2）认知状态的改善是否可以与组织病理学或基于血浆的变化相关。使用在 Thy1 启动子下过表达人野生型α-突触核蛋白（αSyn）的小鼠（Thy1-αSyn 小鼠，“line 61”）作为具有认知能力下降的 PD 模型。从 4 个月大开始，Thy1-αSyn 小鼠用 PNA5 或生理盐水（1mg/kg/天）进行全身治疗，并与 WT 进行 6 个月的行为测试。随后，分析小鼠大脑的病理变化，并使用多重免疫分析法检测外周血中细胞因子的变化。PNA5 治疗逆转了 Thy1-αSyn 小鼠的新型物体识别和 Y 迷宫自发改变所测量的认知功能障碍。PNA5 治疗是针对认知缺陷的，因为精细运动障碍没有改变。认知增强与海马炎症的减少和循环巨噬细胞诱导蛋白（MIP-1β）水平的降低有关。此外，PNA5 治疗还减轻了 αsyn 小鼠 CA3 海马区的神经元丢失。这些数据表明，PNA5 治疗可减少 PD 小鼠模型中的认知功能障碍。这些变化与血浆中 MIP-1β 水平降低有关，提示其可能成为一种潜在的治疗靶点。因此，PNA5 治疗可能有潜力填补 PD 认知能力下降的治疗空白。
