Restoring Immune Function as a Potential Alzheimer’s Therapy

BrightFocus-funded researchers discover a potential new treatment approach for Alzheimer’s - restoring the function of regulatory T cells (Tregs) to control the body’s immune response and suppress Alzheimer’s-associated brain inflammation.

What: BrightFocus-funded researchers discover a potential new treatment approach for Alzheimer’s - restoring the function of regulatory T cells (Tregs) to control the body’s immune response and suppress Alzheimer’s-associated brain inflammation.

Where: Faridar A et al, Restoring regulatory T-cell dysfunction in Alzheimer’s disease through ex vivo expansion, Brain Communications, 2020.

BrightFocus Connection: This project was supported by an Alzheimer’s Disease Research (ADR) grant to first author Alireza Faridar, MD, of Houston (TX) Methodist Research Institute. Senior author Stanley Appel, MD, who co-directs the institute, is a mentor on the grant and one of the world’s leading researchers on amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Dr. Appel’s early research career was supported with a grant from BrightFocus.

Why It Is Important: The role of the immune system is taking on ever-greater significance in Alzheimer’s research. Neuroinflammation can be initiated by a range of factors including trauma, infection, oxidative stress, and a buildup of toxic amyloid beta (Aβ) and tau proteins, leading to chronic inflammation and cell damage. Persistent environmental or internal factors, as well as deficits in immune function, can contribute to sustained inflammation. Through its ADR program, BrightFocus is supporting 14 research projects investigating the factors and mechanisms of inflammation associated with Alzheimer’s disease (AD).

For his BrightFocus project, Dr. Faridar hypothesized that regulatory T cells (Tregs), important immune modulators that suppress the immune response, might lose their function in AD, leading to increased inflammation. His work was among the first to provide evidence of Treg dysfunction in a cell culture model, and he speculated that restoring Treg function through cell therapy could become a novel therapeutic approach for AD-related dementia.

His recent publication details continuing results from this BrightFocus-funded work. In an early proof-of-principle clinical study, Dr. Faridar and colleagues showed that the number of Tregs were decreased in people with Alzheimer’s dementia. To determine whether Tregs derived from people with AD can effectively suppress inflammation, Tregs obtained from study participants were co-cultured with pro-inflammatory macrophages derived from induced pluripotent stem cells (iPSC). Tregs obtained from people with AD were not able to elicit an appropriate immune response compared to people with mild cognitive impairment or healthy controls.

In attempt to restore the immunogenic properties of Tregs isolated from people with AD, Tregs were expanded in a dish in the presence of factors that would amplify their suppressive activity. Expansion of Tregs increased immuno-regulatory genes, suppressed the proliferation of response T cells, and increased suppression of iPSC pro-inflammatory macrophages which, required cell-to-cell contact.

These promising results support Dr. Faridar’s original hypothesis and show that restoring Treg cell function may provide a way to modulate the inflammatory cascade in AD. This therapeutic approach has been successful in treating other neurodegenerative diseases and is currently in Phase 2 clinical trials for the treatment of ALS under the direction of Stanley Appel. s Recently Dr. Faridar received a large grant supported in part by the Gates Foundation for a Phase 2a clinical trial, testing whether this experimental treatment approach might be safe and effective for people with AD.