# Regulatory T Cells in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $768,798

## Abstract

PROJECT SUMMARY
Recent studies have demonstrated that the adaptive immune response plays an important role Alzheimer’s
disease (AD) progression by promoting a pro-inflammatory state in the brain. This inflammatory process involves
T cell and microglial cell activation. Such inflammatory processes are typically suppressed by a subset of T cells
called regulatory T cells (Tregs). Significantly, Treg dysfunction is associated with AD in humans and in mouse
models of AD. In addition to decreased Tregs in AD cases, studies have demonstrated that systemic depletion
of Tregs exacerbates early AD pathology, while an increase in Tregs attenuates early AD pathology in transgenic
mouse models of AD. However, these previous studies come with important caveats. First, all studies involving
Treg depletion focused on studies in young mice at early stages of AD pathology, which may not be a clinically
relevant time-point. Second, studies using FOXP3-DTR mice and diphtheria toxin to selectively deplete Tregs
deplete Tregs everywhere and induce body-wide inflammation. This makes it difficult to assess whether worse
outcomes observed in AD upon “Treg depletion” are specific to an effect of Tregs in the brain or due to massive
systemic inflammation. Moreover, the types of Tregs that accumulate during AD progression, and their functional
role in disease progression, particularly in brain, are also unknown. Thus, major gaps in our knowledge are
(i) what types of Tregs are found in the brain during steady-state and in Alzheimer’s disease and, (ii)
what role Tregs or distinct subsets of Tregs play in ameliorating AD. Our preliminary studies demonstrate
that Tregs in tissues are quite diverse and that distinct Treg subsets occupy inflamed tissues with different
kinetics. Most notably, we identified a novel population of Tregs, called ISG-Tregs, that accumulate in tissues
with IFN-driven inflammation. Previous studies of AD demonstrate that type I IFN is a characteristic of AD, that
it exacerbates neurological damage in AD models, and plays an important role in initiating neuroinflammation
and promoting AD progression. Thus, ISG-Tregs may play a critical role in AD progression. The goal of this
proposal is to identify the subsets of Tregs present in the brain, and identify where those subsets are
located within the brain, during AD progression, and establish murine models to directly test the function
of Tregs and Treg subsets in AD. We will use scRNA-Seq and spatial proteomic/transcriptomic approaches to
characterize Tregs during AD progression. Using a novel Treg reporter/deleter mouse strain that we developed
we will also develop new mouse models that will allow us to study the function of brain Tregs, or select brain
Treg subsets, on AD progression. We will also provide important information regarding the pathological role of
Treg at different stages of AD in vivo. These studies will allow us to characterize the types of Tregs present in
AD, establish their localizati...

## Key facts

- **NIH application ID:** 10842307
- **Project number:** 5R01AG078731-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Michael Archibald Farrar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $768,798
- **Award type:** 5
- **Project period:** 2022-08-16 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842307

## Citation

> US National Institutes of Health, RePORTER application 10842307, Regulatory T Cells in Alzheimer's Disease (5R01AG078731-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10842307. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*