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Graph: Figure 4 Correlation of genewise cell type enrichment measures with PubMed text mining results within cell types. Several gene symbols were chosen for highlighting, including gene symbols that have not been mentioned in a PubMed abstract with that cell type to date (labeled red). For each of the six cell types, i.e. the astrocyte (a), endothelial cell (b), microglia (c), neuron (d), oligodendrocyte (e), and oligodendrocyte precursor cell (f), the top 100 gene symbols most enriched in that cell type are plotted against the number of PubMed abstracts that mention both that gene symbol as well as the corresponding cell type. [Extracted from the article]

Conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of late onset sporadic Alzheimer's disease (LOAD). Mutations and/or differential expression of microglial specific receptors such as TREM2, CD33, and CR3 have been associated with strong increased risk for developing Alzheimer's disease (AD). DAP12 (DNAX-activating protein 12)/TYROBP, a molecule localized to microglia, is a direct partner/adapter for TREM2, CD33, and CR3. We and others have previously shown that TYROBP expression is increased in AD patients and in mouse models. Moreover, missense mutations in the coding region of TYROBP have recently been identified in some AD patients. These lines of evidence, along with computational analysis of LOAD brain gene expression, point to DAP12/TYROBP as a potential hub or driver protein in the pathogenesis of AD. Using a comprehensive panel of biochemical, physiological, behavioral, and transcriptomic assays, we evaluated in a mouse model the role of TYROBP in early stage AD. We crossed an Alzheimer's model mutant APP /PSEN1 (APP/PSEN1) mouse model with Tyrobp mice to generate AD model mice deficient or null for TYROBP ( APP/PSEN1; Tyrobp or APP/PSEN1; Tyrobp ). While we observed relatively minor effects of TYROBP deficiency on steady-state levels of amyloid-β peptides, there was an effect of Tyrobp deficiency on the morphology of amyloid deposits resembling that reported by others for Trem2 mice. We identified modulatory effects of TYROBP deficiency on the level of phosphorylation of TAU that was accompanied by a reduction in the severity of neuritic dystrophy. TYROBP deficiency also altered the expression of several AD related genes, including Cd33. Electrophysiological abnormalities and learning behavior deficits associated with APP/PSEN1 transgenes were greatly attenuated on a Tyrobp-null background. Some modulatory effects of TYROBP on Alzheimer's-related genes were only apparent on a background of mice with cerebral amyloidosis due to overexpression of mutant APP/PSEN1. These results suggest that reduction of TYROBP gene expression and/or protein levels could represent an immune-inflammatory therapeutic opportunity for modulating early stage LOAD, potentially leading to slowing or arresting the progression to full-blown clinical and pathological LOAD. [ABSTRACT FROM AUTHOR]