Dataset Information

Proteomics of ADAM17 and iRhom2 KO microglia using high-performance secretome protein enrichment with click sugars

ABSTRACT: The cell surface receptor TREM2 is a key genetic risk factor and drug target in Alzheimer’s disease (AD). In the brain, TREM2 is expressed in microglia, where it undergoes proteolytic cleavage, linked to AD risk, but the responsible protease in microglia is unknown. Another microglia-expressed AD risk factor is inactive rhomboid 2 (iRhom2, RHBDF2), which acts as a non-catalytic subunit of the metalloprotease ADAM17. Its function in AD is unknown. To determine whether loss of iRhom2 and ADAM17 leads to a reduction of cleavage of additional membrane proteins beyond TNF, we used the ‘high-performance secretome protein enrichment with click sugars’ (hiSPECS) method for mass spectrometry-based secretome analysis (Tüshaus et al, 2020). hiSPECS uses a metabolic labeling with click sugars, which allows to culture cells in the presence of serum or serum-like supplements. Therefore, we have used the murine microglia of wild-type and RHBDF2/iRhom2 KO mice.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Microglial Cell, Microglia

SUBMITTER: Stephan Mueller

LAB HEAD: Dr Stefan F. Lichtenthaler

PROVIDER: PXD054898 | Pride | 2025-03-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	KO_1_Slot2-22_1_423.d.zip	Other
	KO_2_Slot2-25_1_426.d.zip	Other
	KO_3_Slot2-19_1_420.d.zip	Other
	KO_4_Slot2-29_1_418.d.zip	Other
	KO_5_Slot2-24_1_425.d.zip	Other

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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the buildup of amyloid-β and tau protein tangles. Alcohol use has been identified as a risk factor for AD; however, the molecular mechanisms underlying this potential causal link remain elusive. An emerging area of research focuses on the role of microglia, the brain's innate immune cells, in AD pathogenesis, with evidence suggesting that alcohol exposure may prime microglia to exhibit an exaggerated immune response when they are subsequently exposed to proinflammatory stimuli. We used a single 10-day chronic-plus-binge alcohol exposure model in male and female C57BL/J mice aged 8- to 10-weeks old. One month later, tauopathy was induced via adenoviral vector (AAV)-mediated overexpression of h-p301L tau. After 2.5 months, the mice underwent behavioral and cognitive testing. Two weeks later, microglia were collected using fluorescence-activated cell sorting (FACS) and processed for unbiased mass spectrometry and deep proteomic analysis to determine the molecular pathways related to microglial reactivity. Microglia from mice exposed to alcohol in young adulthood exhibited a blunted immune response when challenged with AAV-mediated delivery and accumulation of human tau later in life. This was characterized by decreased expression of MHC II- and interferon-associated proteins and bioinformatic prediction of inhibited inflammation-related pathways in the absence of gross histological, behavioral, or cognitive deficits. These results demonstrate unique, temporally specific microglial reactivity to tau that is modulated by early life alcohol exposure, implicating a microglial response that could negatively affect the mechanisms necessary for tau clearance and potentially exacerbate tau pathogenesis. This study provides novel insights into the long-term effects of early alcohol exposure on microglial function and the complexity of context-dependent microglial involvement in tau pathology. Consideration of early life environmental factors is critical for understanding and potentially mitigating the risk of neurodegenerative diseases, such as AD.

Dataset Information

Proteomics of ADAM17 and iRhom2 KO microglia using high-performance secretome protein enrichment with click sugars

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