TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy

Shane M. Bemiller, Tyler J. McCray, Kevin Allan, Shane V. Formica, Guixiang Xu, Gina Wilson, Olga N. Kokiko-Cochran, Samuel D. Crish, Cristian Lasagna Reeves, Richard M. Ransohoff, Gary E. Landreth, Bruce Lamb

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Background: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. Results: Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. Conclusions: Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies.

Original languageEnglish (US)
Article number74
JournalMolecular Neurodegeneration
Volume12
Issue number1
DOIs
StatePublished - Oct 16 2017

Fingerprint

Tauopathies
Myeloid Cells
Phosphotransferases
Pathology
Neurodegenerative Diseases
Microtubule-Associated Proteins
Amyloid
Alzheimer Disease
Inflammation

Keywords

  • Alzheimers disease
  • Immunity
  • Inflammation
  • Tauopathy
  • TREM2

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. / Bemiller, Shane M.; McCray, Tyler J.; Allan, Kevin; Formica, Shane V.; Xu, Guixiang; Wilson, Gina; Kokiko-Cochran, Olga N.; Crish, Samuel D.; Lasagna Reeves, Cristian; Ransohoff, Richard M.; Landreth, Gary E.; Lamb, Bruce.

In: Molecular Neurodegeneration, Vol. 12, No. 1, 74, 16.10.2017.

Research output: Contribution to journalArticle

Bemiller, SM, McCray, TJ, Allan, K, Formica, SV, Xu, G, Wilson, G, Kokiko-Cochran, ON, Crish, SD, Lasagna Reeves, C, Ransohoff, RM, Landreth, GE & Lamb, B 2017, 'TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy', Molecular Neurodegeneration, vol. 12, no. 1, 74. https://doi.org/10.1186/s13024-017-0216-6
Bemiller, Shane M. ; McCray, Tyler J. ; Allan, Kevin ; Formica, Shane V. ; Xu, Guixiang ; Wilson, Gina ; Kokiko-Cochran, Olga N. ; Crish, Samuel D. ; Lasagna Reeves, Cristian ; Ransohoff, Richard M. ; Landreth, Gary E. ; Lamb, Bruce. / TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. In: Molecular Neurodegeneration. 2017 ; Vol. 12, No. 1.
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