Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology

Wood, Jack,1997Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry (author)

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in mi-croglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer's mouse model with late plaque development. In 18-month-old APPNL-F/NL-F knockin mice, with and without the Alzheimer's disease risk mutation Trem2R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced micro-glial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APPNL-F/NL-FTrem2R47H/R47H mice. These TREM2-depen-dent genes are all involved in phagocytic and degradative processes that we show correspond to a decrease in phagocytic markers and an increase in the density of small plaques in Trem2-mutated mice. Furthermore, despite the R47H mutation preventing increased Trem2 gene expression, TREM2 protein levels and micro-glial density are still marginally increased on plaques. Hence, both microglial contact with plaques and func-tioning TREM2 are necessary for microglia to respond appropriately to amyloid pathology.

Wong, E. (author)
Joghee, R. (author)
Balbaa, A. (author)
Vitanova, K. S. (author)
Stringer, KatieGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xstrkt (author)
Vanshoiack, A. (author)
Phelan, S. L. J. (author)
Launchbury, F. (author)
Desai, S. (author)
Tripathi, T. (author)
Hanrieder, Jörg,1980Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xhanrj (author)
Cummings, D. M. (author)
Hardy, J. (author)
Edwards, F. A. (author)
Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi (creator_code:org_t)

By the author/editor: Wood, Jack, 1997; Wong, E.; Joghee, R.; Balbaa, A.; Vitanova, K. S.; Stringer, Katie; show more...; Vanshoiack, A.; Phelan, S. L. J.; Launchbury, F.; Desai, S.; Tripathi, T.; Hanrieder, Jörg, ...; Cummings, D. M.; Hardy, J.; Edwards, F. A.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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