Abstract
Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia. The human paralog Siglec‐8 was also upregulated on microglia in AD. Siglec‐F and Siglec‐8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV‐2 cell line and human stem cell‐derived microglia models. Siglec‐F overexpression activates an endocytic and pyroptotic inflammatory response in BV‐2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine‐based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV‐2 cells. Collectively, our results point to an important role for mouse Siglec‐F and human Siglec‐8 in regulating microglial activation during neurodegeneration.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease which presently affects over 5.8 million Americans and 55 million people worldwide (Gaugler et al, 2019)
The impact of gliosis on this process is emphasized by recent genome-wide association studies (GWAS) that have uncovered mutations in microglial genes, including TREM2, CD33, and INPP5D, which contribute to disease pathogenesis through phosphorylation signaling (Lambert et al, 2013; Colonna & Wang, 2016; Jansen et al, 2019; Kunkle et al, 2019)
We subsequently performed a deep analysis of the global phosphoproteome on the supernatant from this second IP of cortical tissue, through reverse-phase fractionation followed by immobilized metal affinity chromatography-based pSer/pThr enrichment
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease which presently affects over 5.8 million Americans and 55 million people worldwide (Gaugler et al, 2019). The impact of gliosis on this process is emphasized by recent genome-wide association studies (GWAS) that have uncovered mutations in microglial genes, including TREM2, CD33, and INPP5D, which contribute to disease pathogenesis through phosphorylation signaling (Lambert et al, 2013; Colonna & Wang, 2016; Jansen et al, 2019; Kunkle et al, 2019). There have been few studies of how these signaling proteins affect proteome-wide phosphorylation events, or the phosphoproteome, during neurodegeneration. We aimed to measure and compare the phosphoproteomes of different mouse models of AD in order to understand signaling changes linked to neurodegeneration. We analyzed three separate mouse models of Alzheimer’s disease and neurodegeneration: (i) CK-p25 (Cruz et al, 2003, 2006; Fischer et al, 2005), a model of p25/Cdk activation in forebrain neurons;
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