Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

TY - JOUR

T1 - Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

AU - Agís-Balboa, Roberto Carlos

AU - Pinhero, Paulo

AU - Rebola, Nelson

AU - Kerimoglu, Cemil

AU - Benito, Eva

AU - Gertig, Michael

AU - Bahari-Javan, Sanaz

AU - Jain, Gaurav

AU - Burkhardt, Susanne

AU - Delalle, Ivana

AU - Jatzko, Alexander

AU - Dettenhofer, Markus

AU - Zunszain, Patricia A.

AU - Schmitt, Andrea

AU - Falkai, Peter

AU - Pape, Julius C.

AU - Binder, Elisabeth B.

AU - Mulle, Christophe

AU - Fischer, Andre

AU - Sananbenesi, Farahnaz

PY - 2017/10/2

Y1 - 2017/10/2

N2 - 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.

AB - 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.

KW - Aging

KW - Alzheimer's disease

KW - Formin 2

KW - HDAC inhibitor

KW - Post-traumatic stress disorder

UR - http://www.scopus.com/inward/record.url?scp=85026640250&partnerID=8YFLogxK

U2 - 10.15252/embj.201796821

DO - 10.15252/embj.201796821

M3 - Article

AN - SCOPUS:85026640250

SN - 0261-4189

VL - 36

SP - 2815

EP - 2828

JO - The EMBO journal

JF - The EMBO journal

IS - 19

ER -