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

Abstract

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)

Oligomeric amyloid-β induces early and widespread changes to the proteome in human iPSC-derived neurons

“…Using nLC-MS/MS and LFQ, we investigated the changes to the proteome and phosphoproteome elicited by this oAβ challenge. Using this unbiased approach, we were able to identify a number of proteins of interest that support previous findings 34,35 , but also proteins that extend our current understanding of early amyloid pathology.…”

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