. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11524-11529. Epub 2017 Oct 9 PubMed.


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  1. The papers by the Holtzman and Lamb groups describe how TREM2 plays a protective role in early disease by tamping down tau hyperphosphorylation and aggregation. The results imply that TREM2 normally protects against tau pathology. 

    We would like to add our findings. We reported that TREM2 plays a critical role in inflammation and is essential for neuroplasticity and myelination in an AD transgenic mouse model. We described the presence of TREM2 in oligodendrocytes, in white-matter tracts of the olfactory bulb, corpus callosum, and striatal bundles, indicating that TREM2 protein may have a role in myelination. This would imply that the lack of functioning TREM2 could be a contributing mechanism in myelination deficits seen in neurodegenerative diseases and could increase the susceptibility for neuronal loss. We have shown by primary neuronal and glial culture that TREM2 protein was present in all cells (especially in hippocampal neurons and oligodendrocytes), indicating that TREM2 could be involved in neuroplasticity and neuroprotection (Raha et al., 2016). 

    Using human brain sections from AD and DS we provide evidence, for the first time, that soluble TREM2 originates in bone marrow, is transported to the brain by a subset of macrophages before being taken up by microglia in Down’s syndrome subjects (Raha-Chowdhury et al., 2017, JAD in press). 

    The TREM2 (R47H) mutation, which has been strongly linked with an increased risk of AD, was found in two DS subjects, and in both we observed gross morphological changes in megakaryocytes and erythrocytes. In erythrocytes, we also discovered impairment of TREM2 trafficking to the erythrocyte plasma membrane that could influence the amyloid clearance mechanism thought to be important in AD pathogenesis. TREM2 protein levels in brain and sera declined with age and disease progression in AD and DS.

    Our findings support those observed by the Holtzman group that TREM2 could be neuroprotective, and understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.


    . Neuroprotective Effect of TREM-2 in Aging and Alzheimer's Disease Model. J Alzheimers Dis. 2017;55(1):199-217. PubMed.

    . Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer's Disease Pathology in Down Syndrome. J Alzheimers Dis. 2018;61(3):1143-1162. PubMed.

    View all comments by Ruma Raha-Chowdhury

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