The role of TREM2-positive monocytes in Alzheimer's disease

Bemiller, Shane

Abstract

Alzheimer's disease (AD) is a devastating and debilitating disease affecting millions of people worldwide. AD has been identified as the third leading cause of death, with no treatment options currently available. The main pathological hallmarks of AD are the marked widespread activation of microglia, the resident immune effector cells of the brain, intraneuronal deposits of hyperphosphorylated microtubule associated protein tau (MAPT), and the extracellular aggregation of misfolded amyloid-beta (A?) protein. It is well known that neuroinflammation is intimately involved in the pathogenesis of AD as further evidenced by the recent identification of rare coding alterations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a critical mediator of inflammation and phagocytosis. While it is known that TREM2 is a critical regulator of immunity in the periphery, little is currenly known regarding the role of TREM2 in AD. Our preliminary data points towards the recruitment of peripherally circulating inflammatory monocytes, which throughout the course of pathology cross the blood brain barrier, migrate to plaques, and modulate pathological outcomes of AD. We posit that TREM2 expression is upregulated in AD patients compared to age- matched control individuals and that these TREM2+ cells will have unique inflammatory transcript profiles compared to their non-diseased, control counterparts. We predict that we will determine correlations between levels of amyloid and tau in CSF fluid measurements, as well as a correlation between individuals which harbor the ApoE4 allelic variant, thus allowing us to potentially characterize human blood monocyte TREM2 expression as a potential novel biomarker to aid in the diagnosis of AD. Further, we predict that TREM2 expression grants peripheral monocytes a competitive advantage in either the differentiation, extravasation across the blood brain barrier, or in the homing capacity of cells into the parenchyma. We expect that complete ablation of monocyte TREM2 will ultimately result in a marked decrease in TREM2+ macrophages juxtaposed to senile plaques with concomitant decreases in inflammation as well as amyloid and tau pathologies. We will first identify and characterize the cellular profile of circulating TREM2+ peripheral blood mononuclear cells (PBMCs) in human blood using flow cytometry. Analyzing blood draws from human AD patients and age-matched controls, we expect to determine the population of cells in the periphery which expresses and upregulates TREM2, as well as determine distinct and differentially regulated expression profiles in these populations between AD patients and control individuals, using state of the art RNA sequencing technology. APPPS1 mice will be used to determine the mechanistic function of circulating TREM2+ monocytes in an in vivo model, using flow cytometry, IHC, and basic biochemical assays we aim to determine the localization of these infiltrating cells as well as their role in th progression of AD pathology.

Public Health Relevance

The recent identification of coding alterations in the innate immune receptor TREM2 has further strengthened the idea that Alzheimer's disease (AD) pathogenesis is directly linked to dysregulated neuroinflammation. This proposal seeks to better understand the role of TREM2 on recruited peripherally derived mononuclear phagocytes in the hopes of identifying novel therapeutic treatment options related to modulating CNS inflammation in an attempt to mitigate pathological outcomes in AD patients.