Service de Pharmacologie et d'Immunoanalyse, CEA, Université Paris-Saclay, F-91191, Gif-sur Yvette, France.
Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Sci Rep. 2020 Jan 24;10(1):1143. doi: 10.1038/s41598-020-57560-3.
Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1β expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.
神经退行性疾病，包括阿尔茨海默病和帕金森病，其特征是大脑中蛋白质聚集增加、进行性神经元丧失、炎症增加和神经发生受损。我们使用体内和体外模型分析了新型嘌呤衍生物药物 PDD005 对神经退行性疾病发病机制相关机制的影响。结果表明，PDD005 分布于大脑中，可减轻与衰老相关的认知缺陷。PDD005 通过增加性别决定区 Y 框 2、巢蛋白治疗，还能通过上调突触小体和突触后密度蛋白 95 来增强突触功能，从而预防神经发生受损。PDD005 还通过降低白细胞介素-1β的表达、星形胶质细胞和小胶质细胞的激活来减少神经炎症。我们确定了阻抑蛋白作为 PDD005 治疗衰老小鼠认知缺陷的潜在治疗靶点。此外，在本研究中，糖原合酶激酶似乎能减轻 tau 病理学。
