Lin Yuan, Bai Yang, Martin-Avila Alejandro, Li Wei, Wu Xujun, Ziff Edward, Gan Wen-Biao
Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, NY, NY 10065, USA.
Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China.
Cell Calcium. 2025 Sep;130:103048. doi: 10.1016/j.ceca.2025.103048. Epub 2025 Jul 2.
Presenilin (PS) gene mutations cause memory impairment in early-onset familial Alzheimer's disease (FAD), but the underlying mechanisms remain unclear.
We examined the effects of the PS1 M146V FAD mutation on motor learning, motor learning-related changes in neuronal Caactivity and CREB phosphorylation in the primary motor cortex.
We found that PS1 M146V knock-in mice displayed long-term deficiencies in motor skill learning. Ca levels are altered in a cortical layer and neuron type-specific manner in PS1 mutant mice as compared to WT control mice. Notably, while running caused a significant increase of CREB phosphorylation in WT mice, it led to a significant decrease of CREB phosphorylation in layer 5 neurons of mutant mice.
These findings suggest that alterations of Ca activity and CREB phosphorylation in deep cortical layers are early events leading to memory impairment in the PS1 mutation-related familial form of AD.
早发性家族性阿尔茨海默病（FAD）中早老素（PS）基因突变会导致记忆障碍，但其潜在机制仍不清楚。
我们研究了PS1 M146V FAD突变对运动学习、运动学习相关的神经元钙活性变化以及初级运动皮层中CREB磷酸化的影响。
我们发现PS1 M146V基因敲入小鼠在运动技能学习方面存在长期缺陷。与野生型对照小鼠相比，PS1突变小鼠的钙水平在皮质层和神经元类型上有特异性改变。值得注意的是，跑步导致野生型小鼠中CREB磷酸化显著增加，而在突变小鼠的第5层神经元中却导致CREB磷酸化显著减少。
这些发现表明，皮质深层中钙活性和CREB磷酸化的改变是导致与PS1突变相关的家族性阿尔茨海默病记忆障碍的早期事件。
