Deficiency of TYROBP, an adapter protein for TREM2 and CR3 receptors, is neuroprotective in a mouse model of early Alzheimer’s pathology

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 APP KM670/671NL /PSEN1 Δexon9 (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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1737-3) contains supplementary material, which is available to authorized users.

Alzheimer's disease pathology in Nasu-Hakola disease brains

“…In the present study, three cases of NHD showed the homozygous mutation of c.141delG in exon 3 of DAP12. A recent study showed that deficiency of DAP12 does not modify the number and size of Aβ plaque deposition in the prefrontal cortex and the hippocampus of APP/PSEN1 mice, although DAP12 deficiency reduces plaque compaction, microglial clustering, and phagocytosis (20). Furthermore, phosphorylation of tau is attenuated in female APP/ PSEN1 mice with loss of DAP12.…”

TREM2 triggers microglial density and age‐related neuronal loss

“…Loss of TREM2 in a tau mouse model led to less brain atrophy. Interestingly, deficiency of TYROBP, the adapter protein for TREM2, was neuroprotective in a mouse model of AD (Haure‐Mirande et al, ). The deficiency of TYROBP resulted in an altered expression of AD‐related genes, with less severe neuritic dystrophy and attenuated learning behavior deficits.…”

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

“…Genes relating to TYROBP signaling, which is implicated in Alzheimer's and regulates phagocytosis, cell proliferation, activation and survival, were significantly upregulated (Keren-Shaul et al, 2017;Landreth & Reed-Geaghan, 2009;Ma et al, 2015). Substantiating these findings Tyrobp knockout mice models have proven to suppress inflammation in neurodegenerative models including Alzheimer's, thereby minimizing neuronal dystrophy, implicating a failure in the resolution of inflammation in Alzheimer's(Bakker et al, 2000;Haure-Mirande et al, 2017). Interestingly mutations and expression of downstream members are also linked with…”