Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

Reinders, Niels R.; Pao, Yvonne; Renner, Maria; Silva-Matos, Carla M. Da; Lodder, Tessa R; Malinow, Roberto; Kessels, Helmut W.

doi:10.1073/pnas.1614249113

Cited by 100 publications

(89 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionsupporting

confidence: 76%

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

Hesse

Hurtado

Jackson

et al. 2019

Preprint

View full text Add to dashboard Cite

Highlights 42• Proteomic analysis of synapses isolated from Alzheimer's disease and control subject 43 brains identifies over 5,500 proteins in human synapses. 44• In silico analysis reveals region-specific decreases in proteins involved in synaptic 45 and mitochondrial function and increases in proteins involved in neuroimmune 46 signaling and intracellular signaling in AD. 47• The apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic 48 proteins in AD. 49 50 Abstract 51Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive 52 decline, and synaptic pathology contributes to disease pathophysiology. We recently 53 discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 54 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in 55 human AD brain. To begin to understand the molecular cascades involved in synapse loss in 56 AD and how this is mediated by APOE, and to generate a resource of knowledge of changes 57 in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico 58 analysis of synaptoneurosome preparations from temporal and occipital cortices of human 59 AD and control subjects with known APOE gene status. Our analysis identified over 5,500 60 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-61 associated changes in multiple molecular pathways including a decreased abundance in AD 62 of proteins important for synaptic and mitochondrial function and an increased abundance of 63 proteins involved in neuroimmune interactions and intracellular signaling. 64 65

show abstract

Section: Discussionsupporting

confidence: 76%

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

Hesse

Hurtado

Jackson

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…It has recently been shown that AMPAR density was significantly reduced at perforated synapses and synapses onto parvalbumin-positive neurons in the CA1 region of TARPγ-2 KO mice which is interesting since we found significantly reduced levels of parvalbumin in the hippocampus of both models (Table S3) (Yamasaki et al, 2016). Furthermore, pore forming Gria3 and 4 AMPAR subunits were not found as being significantly altered, however in other AD models they have been showed to be important Aβ substrates (Reinders et al, 2016) ( Figure S5A-B). AMPAR downscaling and removal have been previously described in multiple AD models and has been shown to occur before plaque formation but the precise mechanism explaining these observations have remained vague (Chang et al, 2006;Hsia et al, 1999;Hsieh et al, 2006).…”

Section: Ampars As Candidate Examples For Ad Proteomic Resourcesupporting

confidence: 50%

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

Savas¹,

Wang²,

DeNardo

et al. 2017

Preprint

View full text Add to dashboard Cite

SummaryAmyloid beta (Aβ) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre-and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARPγ-2, a key AMPA receptor trafficking protein. Expression of TARPγ-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD. Highlights• Proteomic analysis of mouse brains with AD-like pathology reveals stark remodeling• Proteomic evidence points to a dysregulation of ApoE levels associated with Aβ clearance rather than production• Co-expression analysis found distinctly impaired synapse and mitochondria modules• In-depth analyses of AMPAR complex points to loss of TARPγ-2, which may compromise synapses in AD eTOC BlurbProteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals Aβ, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimer's disease research community. peer-reviewed)

show abstract

“…Furthermore, pore forming GluA3 and -4 subunits were not significantly altered. In other AD models they have been showed to be important Aβ substrates (Reinders et al, 2016). AMPAR downscaling and removal have been reported in multiple AD models, but the precise mechanism(s) have remained vague (Chang et al, 2006; Hsia et al, 1999; Hsieh et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

et al. 2017

View full text Add to dashboard Cite

SUMMARY Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer’s disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission. Analysis of the AMPA receptor (AMPAR) complex revealed specific loss of TARPγ-2, a key AMPAR trafficking protein. Expression of TARPγ-2 in hAPP transgenic mice restored of AMPA currents. This proteomic database represents a resource for the identification of protein alterations responsible for AD.

show abstract

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

Cited by 100 publications

References 49 publications

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

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

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

Contact Info

Product

Resources

About