@article{88ef896a1e874268ae31c88ca1577202,
title = "Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease",
abstract = "Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single-synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.",
keywords = "AMPA receptor, Alzheimer's disease, Aβ, actin cytoskeleton, immunotherapy, synaptic impairment",
author = "David Baglietto-Vargas and Prieto, {Gilberto Aleph} and Agenor Limon and Stefania Forner and Rodriguez-Ortiz, {Carlos J.} and Kenji Ikemura and Ager, {Rahasson R.} and Rodrigo Medeiros and Laura Trujillo-Estrada and Martini, {Alessandra C.} and Masashi Kitazawa and Davila, {Jose C.} and Cotman, {Carl W.} and Antonia Gutierrez and LaFerla, {Frank M.}",
note = "Funding Information: This study was supported by grants from the Alzheimer{\textquoteright}s Association: NIRG-15-363477 (DBV), AARF-16-440760 (SF), and MNIRGD-15-363229 (CRO); The Larry Hillblom Foundation: 2013-A-016-FEL (DBV) and 2016-A-016-FEL (ACM); the National Institute of Health (NIH): NIH/NIA AG027544 (FML), AG00538 (FML and CWC), OD010420 (FML), AG048506 (CWC), AG053740 (AL); BrightFocus Foundation Grant: A2015535S (FML), University of California and Institute for Mexico: CN-13-613 (AL) and CN-16-170 (GAP); and Institute of Health Carlos III (ISCiii) Grant: PI15/00796 (AG) cofinanced by FEDER Funds from European Union. Funding Information: Funding information This study was supported by grants from the Alzheimer's Association: NIRG-15-363477 (DBV), AARF-16-440760 (SF), and MNIRGD-15-363229 (CRO); The Larry Hillblom Foundation: 2013-A-016-FEL (DBV) and 2016-A-016-FEL (ACM); the National Institute of Health (NIH): NIH/NIA AG027544 (FML), AG00538 (FML and CWC), OD010420 (FML), AG048506 (CWC), AG053740 (AL); BrightFocus Foundation Grant: A2015535S (FML), University of California and Institute for Mexico: CN-13-613 (AL) and CN-16-170 (GAP); and Institute of Health Carlos III (ISCiii) Grant: PI15/00796 (AG) cofinanced by FEDER Funds from European Union. We thank Dr. Malcolm Leissring for his critical review of the manuscript and Celia da Cunha for her technical support. Publisher Copyright: {\textcopyright} 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",
year = "2018",
month = aug,
doi = "10.1111/acel.12791",
language = "English (US)",
volume = "17",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "4",
}