The Role of Microglial-Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) in Neuronal Homeostasis and Tau Pathogenesis

Abstract

The importance of microglia in neurodegeneration has been highlighted by recent identification of microglial genes associated with increased risk for dementia. Among these, several variants of ‘Triggering Receptor expressed on myeloid cells 2’ (TREM2), confer higher risk for different types of dementia including Alzheimer’s disease and frontotemporal-like dementia with early onset. The mechanism by which alterations in TREM2 predisposes individuals to early dementia and how TREM2 influences proteinopathies, especially tauopathy remains unclear. The first part of this thesis focused on the role of TREM2 in neuronal homeostasis using a novel Trem2 p.Y38C mouse model (Trem2Y38C/Y38C) and mice lacking Trem2 (Trem2-/-). Young adult Trem2Y38C/Y38C and Trem2-/- mice exhibited synaptic impairments with reduced long-term potentiation accompanied by oligodendrocyte/myelin impairments. These pathologies are reminiscent of the clinical manifestation in patients with TREM2 p.Y38C mutation and functional loss of TREM2. Since these alterations were detected in wildtype Trem2Y38C/Y38C and Trem2-/- mice in the absence of any pathological insults, these results demonstrate that TREM2 directly impacts neuronal functions and homeostasis independent of the triggers such as pathological tau. In the second part of the thesis, we addressed the role of TREM2 in tau pathogenesis using aforementioned Trem2Y38C/Y38C and Trem2-/- mouse models crossed to human wildtype tau expressing ‘htau’ mice. Loss of functional TREM2 does not alter the overall phosphorylated tau burden but shifts localization of tau to the interstitial fluid in a tau species and sex-dependent manner. Female htau mice lacking functional TREM2 showed lower insoluble tau (largely intracellular) but higher tau levels in the interstitial fluid (extracellular). Transcriptomic analysis reveal alterations in genes associated with neuroinflammation and microglial phagocytic pathways in htau;Trem2Y38C/Y38C and htau;Trem2-/- mice . These alterations likely suggest compromised uptake and/or clearance of extracellular tau leading to the accumulation of tau in the ISF, which has been shown to be detrimental to the synapses. These results demonstrate that TREM2 is important for microglial, neuronal, and white matter functions and provides unique insights on the aspects of tau pathogenesis impacted by TREM2.