Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY 10032, USA.
Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), NYSPI Kolb Research Annex, Room 736, 1051 Riverside Drive, Unit 87, New York, NY 10032, USA.
Int J Mol Sci. 2021 Oct 28;22(21):11637. doi: 10.3390/ijms222111637.
The greatest risk factor for developing Alzheimer's disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water. This regulatable expression allowed for assessment of aging independent of prolonged mutant tau expression. Our results suggest that P301L expression in aged mice enhances memory deficits in the Morris water maze task. These behavioral changes may be due to enhanced late-stage tau pathology, as evidenced by immunoblotting and exacerbated hippocampal dysregulation of glutamate release and uptake measured by the microelectrode array technique. We additionally observed changes in proteins important for the regulation of glutamate and tau phosphorylation that may mediate these age-related changes. Thus, age and P301L tau interact to exacerbate tau-induced detrimental alterations in aged animals.
阿尔茨海默病（AD）发病的最大危险因素是年龄的增长。了解导致衰老大脑更容易患上 AD 的变化，可能会产生新的治疗靶点。为了更好地理解这些变化，本研究利用了携带可调节突变 P301L 人类转基因（rTg（TauP301L）4510）的小鼠，通过在饮用水中添加或去除强力霉素，可以调节 P301L tau 的表达。这种可调节的表达使得可以在不考虑延长突变 tau 表达的情况下评估衰老。我们的研究结果表明，在老年小鼠中表达 P301L 会增强 Morris 水迷宫任务中的记忆缺陷。这些行为变化可能是由于晚期 tau 病理学增强所致，这可以通过免疫印迹和微电极阵列技术测量的海马谷氨酸释放和摄取的失调来证明。我们还观察到与谷氨酸和 tau 磷酸化调节有关的重要蛋白质的变化，这些变化可能介导这些与年龄相关的变化。因此，年龄和 P301L tau 相互作用，加剧了 P301L tau 在老年动物中引起的有害变化。
