Determining if Tregs are Dysfunctional in Alzheimer's Diseases

Project Summary Abstract
Alzheimer disease (AD) is the most common form of dementia that has no cure and few therapeutic
options, and the strongest risk factor for developing AD dementia is aging, an unavoidable event. T cells are
greatly affected during aging as they become comprised of less naïve/resting cells and more terminal
differentiated/senescent cells that can be cytotoxic and produce high amounts of pro-inflammatory cytokines.
Inflammation is known to be an early event in AD with innate microglial activation and an augmented cytokine
production in the CNS and increases in frequency of circulating Th1, TH17 and Th9 inflammatory T-cells.
Functioning in distinct contrast to these inflammatory T cells, are regulatory T cells (Tregs) which are a
small, usually stable, lineage of inhibitory CD4 T cells that expresses the FoxP3 transcription factor and is
essential for maintaining healthy homeostasis and tolerance. Tregs appear to be involved in AD pathology as
most reports have found them to be at low frequency in the AD patient circulation, while mouse AD models
demonstrate that Tregs can affect the disease as the adoptive transfer of Tregs slows disease progression. The
ability of Tregs to down modulate inflammation makes them central to immune resolution and inhibition of
autoimmunity. But Tregs have additional far-reaching activities as they not only can inhibit the activation of
microglia and other immune lineages (B, T, monocyte), but also can initiate tissue repair and recovery. Tregs
have been shown to be neuroprotective in mouse models for brain hemorrhage and for the neurodegenerative
diseases Parkinson’s, ALS, and AD. Excitingly, the administration of wild type Tregs into the APPPS1 AD mouse
model was found to slow disease and also induce recovery of cognition. Yet, only one group has actually isolated
and performed the in vitro functional assays needed to determine if AD patient-derived Tregs are functionally
competent or if their reduced activity would represent a potential therapeutic target. Unfortunately, this study
used suboptimal Treg isolation methods, combined functionally-distinct Treg subsets into a single population,
and analyzed only one parameter to assess Treg function – suppression of target cell proliferation. Thus, it is
crucial that a more comprehensive study be performed to reveal the breadth of potential dysfunction of Tregs in
AD-dementia and expose dysfunction-inducing mechanisms. As our lab routinely examines human Treg function
in disease, we have begun to study AD-Tregs using a high stringency isolation and multi-parameter functional
assay approach that separately interrogates functionally distinct subsets of Tregs isolated from pairs of matched
AD-dementia vs HC PBMCs. Our overarching goal is to uncover if and why Tregs show dysfunction in AD.
Illuminating the mechanisms of Treg deficiency in AD will contribute to future development of Treg-directed
therapies for AD, where optimal Tregs may slow progression, induce tissue repair and restore cognition.

Grant Number: 1R21AG091064-01A1
NIH Institute/Center: NIH
Principal Investigator: CLARE BAECHER-ALLAN