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.

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

CNRS UMR 5297 Bordeaux France

Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases Göttingen Göttingen Germany

Department of Pathology and Laboratory Medicine Boston University School of Medicine Boston MA USA

Department of Psychiatry and Psychotherapy LMU Munich Munich Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Department of Psychosomatics Westpfalzklinikum Kaiserslautern Teaching Hospital University of Mainz Mainz Germany

Department of Translational Research in Psychiatry Max Planck Institute of Psychiatry Munich Germany

Interdisciplinary Institute for Neuroscience University of Bordeaux Bordeaux France

Laboratory of Neuroscience Institute of Psychiatry University of Sao Paulo São Paulo Brazil

Research Group for Genome Dynamics in Brain Diseases Göttingen Germany

Stress Psychiatry and Immunology Laboratory Institute of Psychiatry Psychology and Neuroscience King's College London London UK

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EMBO J. 2017 Oct 2;36(19):2809-2811. doi: 10.15252/embj.201798013. PubMed

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