Koike Riki, Soeda Yoshiyuki, Kasai Atsushi, Fujioka Yusuke, Ishigaki Shinsuke, Yamanaka Akihiro, Takaichi Yuta, Chambers James K, Uchida Kazuyuki, Watanabe Hirohisa, Takashima Akihiko
Laboratory for Alzheimer's Disease, Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo 171-8588, Japan.
Deapartment of Research and Development, MIG (Medical Innovation Group) Inc, Shibuya, Tokyo 150-0031, Japan.
Brain Commun. 2024 Feb 12;6(1):fcad359. doi: 10.1093/braincomms/fcad359. eCollection 2024.
Alzheimer's disease is a devastating disease that is accompanied by dementia, and its incidence increases with age. However, no interventions have exhibited clear therapeutic effects. We aimed to develop and characterize behavioural tasks that allow the earlier identification of signs preceding dementia that would facilitate the development of preventative and therapeutic interventions for Alzheimer's disease. To this end, we developed a 3D virtual reality task sensitive to the activity of grid cells in the entorhinal cortex, which is the region that first exhibits neurofibrillary tangles in Alzheimer's disease. We investigated path integration (assessed by error distance) in a spatial navigation task sensitive to grid cells in the entorhinal cortex in 177 volunteers, aged 20-89 years, who did not have self-reported dementia. While place memory was intact even in old age, path integration deteriorated with increasing age. To investigate the relationship between neurofibrillary tangles in the entorhinal cortex and path integration deficit, we examined a mouse model of tauopathy (P301S mutant tau-overexpressing mice; PS19 mice). At 6 months of age, PS19 mice showed a significant accumulation of phosphorylated tau only in the entorhinal cortex, associated with impaired path integration without impairments in spatial cognition. These data are consistent with the idea that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex. This method may allow the early identification of individuals likely to develop Alzheimer's disease.
阿尔茨海默病是一种伴有痴呆症的毁灭性疾病，其发病率随年龄增长而增加。然而，目前尚无干预措施显示出明确的治疗效果。我们旨在开发并描述一些行为任务，以便能更早地识别出痴呆症之前出现的迹象，从而有助于为阿尔茨海默病开发预防和治疗干预措施。为此，我们开发了一种对内嗅皮质中网格细胞活动敏感的三维虚拟现实任务，内嗅皮质是阿尔茨海默病中最早出现神经原纤维缠结的区域。我们在177名年龄在20至89岁、无自我报告痴呆症的志愿者中，研究了对内嗅皮质中网格细胞敏感的空间导航任务中的路径整合（通过误差距离评估）。尽管即使在老年时位置记忆仍保持完好，但路径整合能力却随着年龄增长而下降。为了研究内嗅皮质中的神经原纤维缠结与路径整合缺陷之间的关系，我们检测了一种tau蛋白病小鼠模型（P301S突变tau蛋白过表达小鼠；PS19小鼠）。在6个月大时，PS19小鼠仅在内嗅皮质中显示出磷酸化tau蛋白的显著积累，这与路径整合受损相关，但空间认知未受损。这些数据与以下观点一致，即路径整合缺陷是由内嗅皮质中磷酸化tau蛋白的积累所致。这种方法可能有助于早期识别可能患阿尔茨海默病的个体。
