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

• Published in: Molecular neurodegeneration Vol. 12; no. 1; p. 74
• Main Authors: 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 A, Ransohoff, Richard M, Landreth, Gary E, Lamb, Bruce T
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16.10.2017; BioMed Central; BMC
• Subjects: Alzheimer's disease; Alzheimers disease; Animal models; Animals; Development and progression; Disease Models, Animal; Genetic aspects; Genetic diversity; Humans; Immunity; Inflammation; Laboratory animals; Membrane Glycoproteins - deficiency; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - metabolism; Mutation; Myeloid cells; Neurodegeneration; Neurodegenerative diseases; Pathology; Phosphorylation; Physiological aspects; Protein Kinases - metabolism; Receptors, Immunologic - deficiency; Signal Transduction - physiology; Tau protein; Tau proteins; tau Proteins - metabolism; Tauopathies - metabolism; Tauopathies - pathology; Tauopathy; TREM2; β-Amyloid; United States; Inflammation; TREM2; Alzheimers disease; Tauopathy; Immunity
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-017-0216-6

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. 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. 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.