A cortical immune network map identifies a subset of human microglia involved in Tau pathology

Patrick, E.; Olah, M.; Taga, M.; Klein, H.-U.; Xu, J.; White, C. C.; Felsky, D.; Gaiteri, C.; Chibnik, L. B.; Mostafavi, S.; Schneider, J. A.; Bennett, D. A.; Bradshaw, E. M.; De Jager, P. L.

doi:10.1101/234351

bioRxiv · 10.1101/234351

A cortical immune network map identifies a subset of human microglia involved in Tau pathology

Patrick, E.·Olah, M.·Taga, M.·Klein, H.-U.·Xu, J.·White, C. C.·Felsky, D.·Gaiteri, C.·Chibnik, L. B.·Mostafavi, S.·Schneider, J. A.·Bennett, D. A.·Bradshaw, E. M.·De Jager, P. L.

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Abstract

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five gene modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 541 subjects from two cohort studies of brain aging. Two of these transcriptional programs - modules 113 and 114 - relate to the accumulation of {beta}-amyloid, while module 5 relates to tau pathology. These modules are also detectable in the human brain's epigenome, where we replicate these associations. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that VASP, a representative module 5 gene, encodes a protein that is upregulated in activated microglia in AD.

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Patrick, E., Olah, M., Taga, M., Klein, H.-U., Xu, J., White, C. C., Felsky, D., Gaiteri, C., Chibnik, L. B., Mostafavi, S., Schneider, J. A., Bennett, D. A., Bradshaw, E. M., De Jager, P. L.. 2017-12-14. A cortical immune network map identifies a subset of human microglia involved in Tau pathology. https://doi.org/10.1101/234351

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