PXD029230

PXD029230 is an original dataset announced via ProteomeXchange.

Title	APOE4 cell-specific mechanisms underlying cerebrovascular disorder precede neuronal and synaptic dysfunction and cognitive deficits in mice
Description	Apolipoprotein E4 (APOE4), the main susceptibly gene for Alzheimer’s disease1–5, exerts cerebrovascular toxicity6 leading to blood-brain barrier (BBB) breakdown in humans7–9 and APOE4 transgenic mice10–13. Moreover, an early BBB dysfunction predicts cognitive decline in humans7. However, the comprehensive large-scale analysis of cell-specific mechanisms underlying APOE4 cerebrovascular disorder and how it relates to neuronal disorder is lacking. Using single-nucleus RNA-sequencing, phosphoproteome and proteome analysis14–17 here we show that APOE4 compared to APOE3 leads to early disruption of the BBB transcriptome in 2-3-month old APOE4 knock-in mice18 followed by dysregulation in protein signaling networks. This includes proteins regulating cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, and transcription and RNA-splicing suggestive of DNA damage in pericytes. Changes in the BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes starting at 2-3 months of age. The BBB breakdown preceded loss of neurites, post-synaptic interactome dysregulation, and behavioral deficits that developed 2-5 months later, and was associated with astrocyte and microglia response protecting BBB integrity. Thus, disruption of the BBB cell-specific signaling mechanisms could be an initial central contributor to APOE4-mediated neuronal disorder, and possibly a major target to correct APOE4-related cognitive deficits.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:54:08.944.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	marcelo coba
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse; Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-20 03:05:23	ID requested
1	2022-08-23 10:19:34	announced
⏵ 2	2023-11-14 08:54:09	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: phosphoproteome,Alzheimer’s disease, signaling networks, single cell RNA-seq, APOE4, BBB breakdown, interactome, blood-brain barrier

Marcelo P. Coba
contact affiliation	Zilkha Neurogenetic Insitute Deprtment of Psychiatry and Behavioral Sciences Department of Physiology and Neuroscience Keck School of Medicine University of Southern California
contact email	coba@usc.edu
lab head
marcelo coba
contact affiliation	USC
contact email	coba@usc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029230
     1. Label: PRIDE project
     2. Name: APOE4 cell-specific mechanisms underlying cerebrovascular disorder precede neuronal and synaptic dysfunction and cognitive deficits in mice