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Abstract
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 APPKM670/671NL/PSEN1Δexon9(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.
Highlights
Conventional wisdom has held that the chronic neuroinflammation associated with late-onset sporadic Alzheimer’s disease (LOAD) may be a secondary or even protective event that occurs in response to Aβ deposition and may occur only in late stages of AD
TYROBP deficiency or absence does not modify the number and size of Aβ plaque depositions nor the number of microglial cells in prefrontal cortex and hippocampus of APP/PSEN1 mice the level of CD68 in hemibrain protein homogenates was lower in APP/PSEN1;Tyrobp−/− as compared with that observed in APP/PSEN1 mice (Figure i, j)
We examined the effects of the different APP/ PSEN1 and Tyrobp genotypes on long-term depression (LTD), a persistent form of plasticity whose expression depends on endocytosis of postsynaptic AMPA-type glutamate receptors (AMPARs) [38]
Summary
Conventional wisdom has held that the chronic neuroinflammation associated with LOAD may be a secondary or even protective event that occurs in response to Aβ deposition and may occur only in late stages of AD. Recent genetic and genomic approaches, as well as computational strategies, have converged on immune-inflammatory pathways as risk factors and as key events in the pathogenesis of late-onset sporadic Alzheimer’s disease (LOAD) [19]. Identified mutations and variants in genes encoding important immune receptors including CD33, CR3 (Complement Receptor 3), and TREM2 (Triggering Receptor Expressed On Myeloid Cells 2), have been genetically linked to LOAD risk, highlighting the potential role of a dysregulated immune response in an early, and perhaps causative role in AD pathogenesis. Unlike autosomal dominant familial Alzheimer’s mutations that promote elevation of the Aβ42:40 ratio or of other variant hyperaggregatable Aβ species, these AD risk factors specify some of the cell surface signal transduction pathways that modulate the phagocytic machinery of microglia
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