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

Jack I Wood; Eugenia Wong; Ridwaan Joghee; Aya Balbaa; Karina S Vitanova; Katie M Stringer; Alison Vanshoiack; Stefan-Laural J Phelan; Francesca Launchbury; Sneha Desai; Takshashila Tripathi; Jörg Hanrieder; Damian M Cummings; John Hardy; Frances A Edwards

doi:10.1016/j.celrep.2022.111686

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

Cell Rep. 2022 Nov 22;41(8):111686. doi: 10.1016/j.celrep.2022.111686.

Authors

Affiliations

¹ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V3, 43180 Mölndal, Sweden.
² Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
³ Nanostring Technologies, 530 Fairview Avenue N, Seattle, WA 98109, United States.
⁴ Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁵ Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V3, 43180 Mölndal, Sweden.
⁶ Dementia Research Institute, University College London, Gower Street, London WC1E 6BT, UK; Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁷ Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, UK; Institute of Healthy Ageing, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: f.a.edwards@ucl.ac.uk.

PMID: 36417868
DOI: 10.1016/j.celrep.2022.111686

Abstract

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer's mouse model with late plaque development. In 18-month-old APP^NL-F/NL-F knockin mice, with and without the Alzheimer's disease risk mutation Trem2^R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced microglial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APP^NL-F/NL-FTrem2^R47H/R47H mice. These TREM2-dependent 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 microglial density are still marginally increased on plaques. Hence, both microglial contact with plaques and functioning TREM2 are necessary for microglia to respond appropriately to amyloid pathology.

Keywords: Alzheimer’s disease; App(NL-F/NL-F); CP: Neuroscience; NLF mouse; PIGs; Trem2; Trem2(R47H); astrocytes; knockin mouse; microglia; spatial transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
Amyloidogenic Proteins / metabolism
Amyloidosis*
Animals
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mice
Microglia / metabolism
Plaque, Amyloid / metabolism
Receptors, Immunologic / genetics
Receptors, Immunologic / metabolism

Substances

Amyloidogenic Proteins
Trem2 protein, mouse
Membrane Glycoproteins
Receptors, Immunologic

Abstract

Publication types

MeSH terms

Substances

Grants and funding