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Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models.

ABSTRACT: BACKGROUND:Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer's disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. METHODS:In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts. RESULTS:Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD. CONCLUSIONS:The comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies.

SUBMITTER: Sekiya M

PROVIDER: S-EPMC5875009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDelirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer's disease.MethodsWe analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery (n = 120), and some of the patients developed delirium (n = 65). A medical delirium cohort (n = 26) was also examined. ELISA was used to determine the level of sTREM2 in CSF.ResultsDelirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia (p = 0.046, n = 15, n = 44), particularly among patients developing delirium after CSF sampling (p = 0.02, n = 7, n = 44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery (rS = 0.39, p = 0.002, n = 60) and correlated well with the CSF Alzheimer's disease biomarkers, Aβ42, and t-tau/p-tau (rS = 0.40, p = 0.002, rS = 0.46, p < 0.001/ rS = 0.49, p < 0.001, n = 60). Among patients with dementia, the level of Aβ38 and Aβ40 also correlated positively with sTREM2 in CSF (Aβ38MSDrS = 0.44, p = 0.001; Aβ40MSDrS = 0.48, p < 0.001; Aβ42MSDrS = 0.43, p < 0.001, n = 60).ConclusionThe findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk.

Project description: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.

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Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models.

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