Abstract
SummaryAlzheimer'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.
Highlights
The pathobiology of Alzheimer’s disease (AD) is complex and involves changes in many different cellular process, such as alterations in the blood–brain barrier (BBB), synaptic function, metabolic process, oxidative stress, and inflammation (Forner, Baglietto-Vargas, Martini, Trujillo-Estrada & LaFerla, 2017)
To further demonstrate that the early synaptic alterations observed are associated with Ab, we investigated whether dendritic spines were affected in the dentate gyrus of the hippocampus, which does not contain Ab or tau pathology in 7- to 8-month-old 3xTg-AD mice (Figure S7A)
Our current study demonstrates a relationship between Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) activity and p21-activated kinase (PAK) levels, which are in agreement with these previous findings
Summary
The pathobiology of Alzheimer’s disease (AD) is complex and involves changes in many different cellular process, such as alterations in the blood–brain barrier (BBB), synaptic function, metabolic process, oxidative stress, and inflammation (Forner, Baglietto-Vargas, Martini, Trujillo-Estrada & LaFerla, 2017) Among these pathological processes, new evidence from epidemiological studies suggests that synaptic loss is the best predictor of the clinical symptoms of patients with AD (Penzes, Cahill, Jones, VanLeeuwen & Woolfrey, 2011; Selkoe, 2002; Walsh & Selkoe, 2004). One of the most significant structural changes that occur during learning, memory, and other cognitive processes is the restructure of dendritic spines (Parajuli, Tanaka & Okabe, 2016) Given their important role in neuronal plasticity, defects specific to dendritic spines are likely to play a critical role in the synaptic and cognitive impairments associated with AD. Ab immunotherapy reversed the synaptic defects observed in the 3xTgAD mice, suggesting that an earlier intervention is a promising therapeutic approach
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