Formin 2 Links Neuropsychiatric Phenotypes At Young Age To An Increased Risk For Dementia

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia. Role of Fmn2 gene for PTSD like phenotypes and impairments of synaptic plasticity.与年龄相关的记忆衰退，由遗传与环境风险因素的可变组合共同导致。目前学界尚未明确这些风险因素如何相互作用以推动疾病发作。本研究旨在阐明幼年时期罹患创伤后应激障碍（post-traumatic stress disorder, PTSD）如何提升老年痴呆症发病风险的具体机制。我们发现，肌动蛋白成核因子Formin 2（Fmn2）在PTSD患者与阿尔茨海默病（Alzheimer's disease, AD）患者体内均存在表达失调现象。缺失Fmn2基因的幼年小鼠会表现出类PTSD表型以及相应的突触可塑性损伤，但新记忆的巩固过程并未受到影响。然而，Fmn2突变小鼠会出现加速的年龄相关性记忆衰退，且在额外风险因素存在的情况下该衰退程度会进一步加剧，该现象在机制上与转录稳态的丧失密切相关。综上，本研究数据为探索生命周期内AD风险因素之间的关联提供了全新研究思路，并为幼年时期神经精神疾病如何影响痴呆发病风险的相关过程提供了机制层面的深入解析。Fmn2基因在类PTSD表型与突触可塑性损伤中的作用。