Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease
Year: 2018
Type: article
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.
Source: Aging Cell
DOI: 10.1111/acel.12791
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Awards: Behavioral and Neural Plasticity in the Aged, A Neurolucida and Stereo Investigator Imaging System with MicroLucida, G1883455192, Molecular mechanisms of synaptic degeneration in Alzheimer’s disease, G2546058270, Synaptic imbalance in mild cognitive impairment and Alzheimer's Disease, G315073359, G3759868739, Impact of the actin cytoskeleton and its regulators in Alzheimer’s disease, Impact of diabetes on tau pathology and cognition in AD transgenic mice, G551826375, Astrocyte-enriched miR181 impact on neuronal plasticity and memory in Alzheimer's Disease, G6241287090, Learning and Memory Impairments in Transgenic AD Models, A Novel Approach to Study Synaptic Plasticity in Isolated Synaptosomes using Flow Cytometry, G741062372, Evaluando la disfunción microglial y astroglial como base del proceso neurodegenerativo y la demencia en la enfermedad de Alzheimer: nuevas aproximaciones terapéuticas, G819710145, G9000119970, G922941218
OpenAlex ID: W2806208316