Department of Pharmacology, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima 731-0153, Japan
Department of Aging Science and Pharmacology
CNS Neurol Disord Drug Targets. 2020;19(7):495-502. doi: 10.2174/1871527319666200708125130.
Many efforts have been made to develop therapeutic agents for Alzheimer's Disease (AD) based on the amyloid cascade hypothesis, but there is no effective therapeutic agent at present. Now, much attention has been paid to infiltrate pathogens in the brain as a trigger of AD. These pathogens, or their virulence factors, may directly cross a weakened blood-brain barrier, reach the brain and cause neurological damage by eliciting neuroinflammation. Moreover, there is growing clinical evidence of a correlation between periodontitis and cognitive decline in AD patients. Recent studies have revealed that microglial cathepsin B is increasingly induced by lipopolysaccharide of Porphylomonas gingivalis, a major pathogen of periodontal disease. Moreover, gingipains produced by P. gingivalis play critical roles in neuroinflammation mediated by microglia and cognitive decline in mice. Furthermore, an orally bioavailable and brain-permeable inhibitor of gingipain is now being tested in AD patients. It is largely expected that clinical studies countering bacterial virulence factors may pave the way to establish the prevention and early treatment of AD.
许多基于淀粉样蛋白级联假说的阿尔茨海默病（AD）治疗药物的研发已取得诸多进展，但目前尚无有效的治疗药物。目前，人们越来越关注大脑内浸润病原体作为 AD 的触发因素。这些病原体或其毒力因子可能通过引发神经炎症，直接穿过薄弱的血脑屏障，到达大脑并造成神经损伤。此外，牙周炎与 AD 患者认知能力下降之间存在相关性的临床证据越来越多。最近的研究表明，牙龈卟啉单胞菌的脂多糖可逐渐诱导小胶质细胞组织蛋白酶 B 的产生，牙龈卟啉单胞菌是牙周病的主要病原体。此外，牙龈卟啉单胞菌产生的牙龈蛋白酶在小胶质细胞介导的神经炎症和小鼠认知能力下降中发挥关键作用。目前，一种可口服且可穿透血脑屏障的牙龈蛋白酶抑制剂正在 AD 患者中进行临床试验。人们普遍期望，针对细菌毒力因子的临床研究可能为 AD 的预防和早期治疗铺平道路。
