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Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer’s disease patient brain samples

Abstract

Identification of multiple immune-related genetic risk factors for sporadic AD (sAD) have put the immune system center stage in mechanisms underlying this disorder. Comprehensive analysis of microglia in different stages of AD in human brains revealed microglia activation to follow the progression of AD neuropathological changes and requiring the co-occurrence of beta-Amyloid (Aβ) and tau pathology. Carriers of AD-associated risk variants in TREM2 (Triggering receptor expressed on myeloid cells 2) showed a reduction of plaque-associated microglia and a substantial increase in dystrophic neurites and overall pathological tau compared with age and disease stage matched AD patients without TREM2 risk variants. These findings were substantiated by digital spatial profiling of the plaque microenvironment and targeted gene expression profiling on the NanoString nCounter system, which revealed striking brain region dependent differences in immune response patterns within individual cases. The demonstration of profound brain region and risk-variant specific differences in immune activation in human AD brains impacts the applicability of immune-therapeutic approaches for sAD and related neurodegenerative diseases.

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Acknowledgements

This work was supported by a supplement to NIH/NIA P30 AG010124 (J.Q.T.) to S.P. We thank Teresa Schuck, John Robinson and Catherine Casalnova for excellent technical support.

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SP, KRM, JQT, and VYML conceived the study and co-wrote the manuscript. SP and KRM supervised and performed experiments. SN, LC, KH, SRL, and RMP performed biochemical experiments. RMP, SRL, KH, SP, and KRM performed histological experiments. SP and KRM performed gene expression analysis and Nanostring nCounter experiments. AR performed GeoMx analysis. SP and KRM performed microglia analysis. SP performed digital image analysis. SP and JQT quantified and confirmed neuropathological changes. JQT and VYML supervised the study.

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Correspondence to Stefan Prokop or John Q. Trojanowski.

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K.R.M. and A.R. are employees of Nanonstring.

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Prokop, S., Miller, K.R., Labra, S.R. et al. Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer’s disease patient brain samples. Acta Neuropathol 138, 613–630 (2019). https://doi.org/10.1007/s00401-019-02048-2

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Keywords

  • Microglia
  • Alzheimer’s disease
  • Neuropathology
  • TREM2