PXD053544

PXD053544 is an original dataset announced via ProteomeXchange.

Title	Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
Description	The strongest risk factors for Alzheimer’s disease (AD) include the 4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that the R47H variant induces neurodegeneration in 9- to- 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:58:17.393.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simone Sidoli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-01 19:42:05	ID requested
1	2024-09-13 10:34:01	announced
⏵ 2	2024-10-22 06:58:17	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: AD, APOE, inflammation, interferon, cGAS, tau, R47H, microglia, TREM2, senescence

Simone Sidoli
contact affiliation	Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, United States
contact email	simone.sidoli@einsteinmed.edu
lab head
Simone Sidoli
contact affiliation	Albert Einstein College of Medicine
contact email	simone.sidoli@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/08/PXD053544

PRIDE project URI

• PRIDE
  1. PXD053544
     1. Label: PRIDE project
     2. Name: Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model