PXD063383

PXD063383 is an original dataset announced via ProteomeXchange.

Title	Plaque induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease
Description	Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques can be either neuroprotective or neurotoxic. Here we show that the protective function of microglia is associated with and functionally linked to a transcriptional shift toward lymphoid gene expression. Microglial contact with the plaques induces downregulation of PU.1, a lineage-specifying transcription factor. PU.1 downregulation plays a key role in mitigating the severity of AD, as evidenced by a reduction in neurotoxic microglia activation, preservation of neuronal connections, maintenance of cognitive function, and increased survival in mice with genetically reduced PU.1 expression in microglia. The neuroprotective effect of PU.1 downregulation is linked to the de-repression of lymphoid-specific proteins, particularly CD28—a surface protein critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed exclusively in a small subset of plaque-associated PU.1low microglia, promotes an inflammatory microglial state and associated increase in amyloid plaque load. Our findings suggest that PU.1low lymphoid/CD28-expressing microglia that emerge in response to AD pathology exert a suppressive, anti-inflammatory effect during AD. This novel role of CD28 -and potentially other lymphoid co-stimulatory or co-inhibitory receptor proteins- in governing microglia responses in AD points to possible new immunotherapy approaches for AD treatment.
HostingRepository	PRIDE
AnnounceDate	2025-08-08
AnnouncementXML	Submission_2025-08-07_17:52:19.139.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Felix Weiss
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-28 01:19:04	ID requested
⏵ 1	2025-08-07 17:52:19	announced

Dataset with its publication pending

submitter keyword: Alzheimer's,microglia, LC-MS/MS

Felix Meissner
contact affiliation	Institute of Innate Immunity, University Hospital Bonn
contact email	fmeissner@uni-bonn.de
lab head
Felix Weiss
contact affiliation	University Hospital Bonn
contact email	fweiss@uni-bonn.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD063383
     1. Label: PRIDE project
     2. Name: Plaque induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease