Modified Glutamatergic Postsynapse in Neurodegenerative Disorders

Moraes, Bruno José; Coelho, Patrícia; Fão, Lígia; Ferreira, Ildete L.; Rego, A. Cristina

doi:10.1016/j.neuroscience.2019.12.002

Cited by 19 publications

(15 citation statements)

References 276 publications

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“…It has been shown that soluble Aβ oligomers promote AMPAR internalization and degradation ( Guntupalli et al., 2017 ; Miñano-Molina et al., 2011 ). This is consistent with studies of our own, and those of others, which show an increase in ubiquitination of AMPARs in AD ( Guntupalli et al., 2017 ; Rodrigues et al., 2016 ; Zhang et al., 2018 ) (as reviewed by Harris et al, 2020 ; Moraes et al., 2020 ; Zhu and Tsai, 2020 ). Findings from our recent work have revealed for the first time that AMPARs are also subject to acetylation, a new form of AMPAR regulation that antagonizes receptor ubiquitination due to competition for the same lysine residues ( Wang et al., 2017 ).…”

Section: Discussionsupporting

confidence: 94%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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Summary In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

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Section: Discussionsupporting

confidence: 94%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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“…Synapses and particularly post-synaptic regions are known to be acutely ROS-sensitive neural subcompartments 55 , suggesting that the highly significant enrichments we observe are required to reduce ROS at these sites. Thus, our findings add to the growing evidence for mitochondrial dysfunction at post-synaptic sites as a driver of neurodegeneration 56 .…”

Section: Discussionsupporting

confidence: 70%

Human brain mitochondrial-nuclear cross-talk is cell-type specific and is perturbed by neurodegeneration

Fairbrother-Browne

et al. 2021

Preprint

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Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases as mitochondria are essential to neuronal function. The mitochondrial genome encodes a small number of core respiratory chain proteins, whereas the vast majority of mitochondrial proteins are encoded by the nuclear genome. Here we focus on establishing a profile of nuclear-mitochondrial transcriptional relationships in healthy human central nervous system tissue data, before examining perturbations of these processes in Alzheimer&#8217s disease using transcriptomic data originating from affected human brain tissue. Through cross- central nervous system analysis of mitochondrial-nuclear gene pair relationships, we find that the cell type composition underlies regional variation, and variation is driven at the subcellular level by heterogeneity of nuclear-mitochondrial coordination in post-synaptic regions. We show that nuclear genes causally implicated in sporadic Parkinson&#8217s disease and Alzheimer&#8217s disease show much stronger relationships with the mitochondrial genome than expected by chance, and that nuclear-mitochondrial relationships are significantly perturbed in Alzheimer&#8217s disease cases, particularly amongst genes involved in synaptic and lysosomal pathways. Finally, we present MitoNuclearCOEXPlorer, a web tool designed to allow users to interrogate and visualise key mitochondrial-nuclear relationships in multi-dimensional brain data. We conclude that mitochondrial-nuclear relationships differ significantly across regions of the healthy brain, which appears to be driven by the functional specialisation of different cell types. We also find that mitochondrial-nuclear co-expression in critical pathways is disrupted in Alzheimer&#8217s disease, potentially implicating the regulation of energy balance and removal of dysfunctional mitochondria in the etiology or progression of the disease and making the case for the relevance of bi-genomic co-ordination in the pathogenesis of neurodegenerative diseases.

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“…The pathological features of AD are related to abnormal synaptic plasticity, which can be affected by the accumulation of Aβ plaques (Sun et al, 2019). Postsynaptic density (PSD) is a complex subcellular domain that forms an essential protein network and modulates synaptic plasticity (Moraes et al, 2021). We found that both the length and width of the PSD were shorter in the AD mice compared with the WT mice (Figures 2A-2C, Figure S2A; p<0.01).…”

Section: Resultsmentioning

confidence: 99%

“…Postsynaptic density (PSD) is a complex subcellular domain that forms an essential protein network and modulates synaptic plasticity (Moraes et al, 2021). We found that both the length and width of the PSD were shorter in the We performed RNA sequencing with mice hippocampi to identify key biological processes and pathways that might be altered by IF.…”

Section: If Improves Synapse Ultrastructure and Alters The Expression...mentioning

confidence: 99%

Intermittent fasting mitigates cognitive deficits in Alzheimer’s disease via the gut-brain axis

Jia

Shi

Zhao

et al. 2022

Preprint

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SummaryIntermittent fasting (IF) is suggested to mitigate cognitive impairment in Alzheimer’s disease (AD). We detailed the effects of IF in AD development and assessed the contribution of the gut microbiota-metabolite-brain axis in promoting the effects of fasting. A 16-week IF regimen significantly improved spatial memory and cognitive function in AD transgenic mice; this improvement was accompanied by decreased Aβ accumulation and suppression of neuroinflammation. IF reshaped the microbiota and beneficially altered the microbial metabolites related to cognitive function. Multi-OMICs integration demonstrated a strong connection between IF induced changes in hippocampus gene expression, the composition of the gut microbes, and the serum metabolites beneficial for cognitive function. Removal of gut microbes with antibiotics abolished the neuroprotective effects of IF. These findings suggest new avenues for therapy and nutritional intervention to prevent the development of AD and other neurodegenerative diseases.

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Modified Glutamatergic Postsynapse in Neurodegenerative Disorders

Cited by 19 publications

References 276 publications

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

Human brain mitochondrial-nuclear cross-talk is cell-type specific and is perturbed by neurodegeneration

Intermittent fasting mitigates cognitive deficits in Alzheimer’s disease via the gut-brain axis

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