Yongyi Li

Program: Neurosciences

Current advisor: David M. Holtzman, MD

Undergraduate university: University of North Carolina-Chapel Hill, 2023

Enrollment year: 2023

Research summary
I study the role of the adaptive immune system in a tauopathy mouse model. Specifically, I study how regulatory T cells, a type of immunosuppressive T cell, can modulate disease pathology in tau-mediated neurodegeneration.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and is the leading cause of dementia in the world. Classically, AD is defined as a proteinopathy, characterized by the extracellular deposition of amyloid-beta (Ab) plaques and the intracellular accumulation of hyperphosphorylated tau tangles, both of which play central roles in AD pathogenesis. Ab accumulation begins in the neocortex 15~20 years preceding the onset of cognitive decline in AD, and strong evidence suggests that it is the first step of the pathogenic cascade. Amyloid deposition can drive tau aggregation, which usually starts in the temporal lobe and then spreads to various neocortical regions roughly at the onset of cognitive decline. Importantly, the progression of tau pathology strongly correlates with neuronal and synapse loss, brain atrophy, and neurodegeneration, ultimately leading to dementia. The Holtzman lab has previously generated a P301S tau transgenic mouse line expressing different isoforms of human APOE, among which hAPOE4 knock-in (TE4) produced the greatest pathology and neurodegeneration. The TE4 mouse model recapitulates various aspects of tau-mediated neurodegeneration that are present in AD and other types of primary tauopathies, including tau pathology and regional brain atrophy in the hippocampus and piriform/entorhinal cortex.

Over the past decade, the role of the CNS innate immune cells, namely microglia, in AD pathogenesis has been put under intense investigation. Genetic and functional evidence have established microglia and, by extension, neuroinflammation, as key drivers of tau-mediated neurodegeneration. Accumulating evidence also suggested that the adaptive immune cells, namely T cells, is associated with tau pathology. The Holtzman lab has previously demonstrated that TE4 mice, but not mice with Ab pathology, developed a unique immunological milieu in the brain. Notably, T cells, especially CD8+ T cells with enrichments of interferon (IFN)-γ transcripts, were markedly increased in brain regions with severe tau pathology and atrophy in TE4 mice. T cell counts in these regions positively correlated with the extent of regional brain atrophy, and T cells dynamically shifted from an activated to an exhausted transcriptomic state, accompanied by increased TCR clonality. Depletion of microglia or T cells, as well as IFN-γ inhibition, significantly rescued neurodegeneration. These results highlighted that microglia-T cell interactions actively drove disease pathology in tau-mediated neurodegeneration. More recently, a unique population of immunosuppressive regulatory T cells (Tregs) resident in the homeostatic meninges was discovered. These Tregs inhibited IFN-γ production by meningeal lymphocytes and subsequently prevented T-cell invasion into the brain parenchyma, thereby restraining local inflammation and preserving brain homeostasis at the steady state. Similarly, other studies have implicated brain Tregs to be immunosuppressive and protective in neuroinflammatory conditions. Collectively, these findings led to my central hypothesis that Tregs in the brain and meninges restrain the infiltration of pathogenic T cells, thereby limiting disease pathology in a mouse model of tau-mediated neurodegeneration.

Graduate publications
Li Y, Ulrich JD, Holtzman DM. 2026 Adaptive immunity in the pathogenesis of neurodegeneration. Nat Immunol, 27(7):1375-89