Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration

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.

Co-expression network analysis of human tau-transgenic mice reveals protein modules associated with tau-induced pathologies

“…Aberrant phosphorylation, such as the hyperphosphorylation of tau protein, plays a key role in AD pathology ( Bai et al., 2020 ; Morshed et al., 2020 ; Perluigi et al., 2016 ; Zhang et al., 2019 ). Thus, in order to support the insights obtained in our WGCNA, we subsequently conducted a phosphoproteomics study of the spinal cord, which presented the most severe tau-induced neuronal damage.…”

1-L Transcription in Alzheimer’s Disease

“…Mice do not express Siglec-8, but Siglec-F is a likely functional orthologue of Siglec-8. Siglec-F was upregulated on a subset of reactive microglia in models of neurodegeneration, and it was observed that Siglec-F is dependent on Aβ deposition at early AD stages [ 32 , 33 ].…”

Pathogenesis, therapeutic strategies and biomarker development based on “omics” analysis related to microglia in Alzheimer’s disease

“…Morshed et al identified signaling pathways that were dysregulated in various mouse models of AD using quantitative phosphoproteomics and found that Siglec-F was upregulated as a shared response in a subset of reactive microglia [ 114 ]. The levels of the human paralog, Siglec-8, were also increased in aged human microglia and in the microglia of patients with LOAD [ 114 ]. Previous studies showed Siglec-F is an eosinophil surface receptor, and Siglec-8 is expressed by human eosinophils.…”

“…Genetic knockout of Siglecf lead to increased inflammation in asthma [ 115 ], indicating that Siglec-F mediated an immune response. An in vitro study showed that both Siglec-F and Siglec-8 were upregulated following microglial activation, and Siglecf overexpression activated an endocytic and pyroptotic inflammatory response in BV-2 cells, a mouse microglial cell line [ 114 ]. The functions and mechanisms of Siglec-F and Siglec-8 are unclear; therefore, whether their upregulation on microglia during aging and AD are secondary to microglial activation, or whether they mediate microglial inflammatory pathways, requires further investigation.…”