Characterization of TREM2-related pathogenic macrophages in aging and diseased peripheral nerves

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Aging is a major risk factor for the functional and structural decline of the nervous system. We have previously shown that also peripheral nerves are structurally and functionally affected by aging. In cross sections, myelinated axons of aging nerves show both changes in their initially rounded shape as well as signs of demyelination. While changes in axonal shape occur independently of inflammation, we identified nerve macrophages as robust drivers for aging-related demyelination. The latter process is reminiscent of demyelinating features previously described by our group in genetically diseased nerves. Interestingly, TREM2, a usually modulating molecule, is necessary for the demyelinating processes. In the present project we aim to characterize the molecular features of pathogenic macrophages in aging and diseased nerves. For this purpose, we will compare the transcriptome of isolated and presorted nerve macrophages by single-cell RNA sequencing. We will compare macrophages from aging and genetically diseased nerves with nerve macrophages of normal adult mice. The comparison with non-pathogenic nerve macrophages of normal and aging TREM2-deficient nerves and TREM2-deficient, genetically diseased nerves will likely be instrumental for identifying core signature genes of pathogenic macrophages. Validation experiments will be performed to investigate whether the identified pathogenic macrophages are indeed localized at pathogenetically-relevant compartments, like the interface between basal laminae and outer Schwann cell membranes of demyelinating fibers. Finally, we will test the hypothesis that pathogenic macrophages are of monocytic origin, using appropriate mutants for fate mapping. Our studies aim to gain novel insights into the cellular and molecular pathogenesis of aging and diseased peripheral nerves.