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

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.

miR‐181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer’s disease

“…Furthermore, the protein levels of GluA2, PSD95, GluA1, and translin were significantly lower in hippocampal synaptosome samples from 3xTg‐AD animals (Figure b–c). These observations are in agreement with other reports showing synaptic impairments in the 3xTg‐AD model (Baglietto‐Vargas et al, ; Caccamo, Maldonado, Bokov, Majumder, & Oddo, ; Clark et al, ; Oddo et al, ).…”

“…cLTP = chemical long-term potentiation; Aβo = amyloid-beta oligomers protein levels of GluA2, PSD95, GluA1, and translin were significantly lower in hippocampal synaptosome samples from 3xTg-AD animals(Figure 4b-c). These observations are in agreement with other reports showing synaptic impairments in the 3xTg-AD model(Baglietto-Vargas et al, 2018;Caccamo, Maldonado, Bokov, Majumder, & Oddo, 2010;Clark et al, 2015;Oddo et al, 2003).2.6 | Augmented protein levels of the AMPA receptor subunits GluA2 and GluA1 are observed in hippocampal crude synaptosome preparations of 3xTg-AD mice after miR-181a inhibitionThen, we examine the molecular mechanisms elicited by miR-181a inhibition in synapses of 3xTg-AD animals. For this, we infused viral particles containing a double-strand RNA sequence against miR-181a or a no related control sequence into the hippocampus of 10-month-old 3xTg-AD mice.…”

“…We have previously reported a significant elevation of miR‐181a in the hippocampus of 3xTg‐AD mice in pathology‐ and age‐dependent manners (Rodriguez‐Ortiz et al, ). Robust evidence supports that Aβ oligomers (Aβo) disrupt LTP (Baglietto‐Vargas et al, ; Lambert et al, ; Walsh et al, ), reviewed in Viola and Klein (). Thus, we treated primary hippocampal cultures with 100 nM Aβo for two hours and analyzed miR‐181a levels and plasticity‐related proteins one hour after cLTP stimulation.…”

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

“…We observed that multiple pathways including those associated with synaptic and mitochondrial function were downregulated with increasing vulnerability and other pathways including intracellular signalling and neuroimmune signalling proteins were increased with increasing vulnerability. This is encouraging as dysfunctional synaptic signalling is consistent with multiple lines of evidence from AD animal models 8, 34, 35 . Some of the proteins that we observe are reduced in AD synapses have been observed as CSF biomarkers associating with disease.…”

The Role of Neuronal Pentraxin 2 (NP2) in Regulating Glutamatergic Signaling and Neuropathology

“…However, while the increase in TACE and LTD may be a compensatory method of coping with the increased αβ burden, it also increases the presence of pro-inflammatory factors as TACE continues to cleave other molecules (Qian et al, 2016) exacerbating neuronal damage. Overall, the increase in NP2 and NP1, the increase of membranebound NPR, and the inactivation of TACE suggests improper AMPA trafficking (Baglietto-Vargas et al, 2018) that relies on pentraxin-dependent mechanisms.…”