Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

Aging Cell. 2018 Aug;17(4):e12791. doi: 10.1111/acel.12791. Epub 2018 Jun 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Animals
  • Cytoskeleton / metabolism*
  • Disease Models, Animal*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Signal Transduction*
  • Synaptic Transmission*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism*


  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid