(523) Inflammation in aging and Alzheimer’s progression is marked by dysfunctional T-regulatory cell states

Introduction/Rationale: Aging and Alzheimer’s disease (AD) are marked by progressive brain inflammation. Microglia can become sensitized during aging, potentiating immune activation. T-regulatory (Treg) cells, which help restrain inflammation by suppressing microglial activation, likely play a crucial role in the progression of Alzheimer’s and aging, but their activity remains poorly understood. In this study, we elucidate mechanisms of immune activation by classifying microglia and Treg activity in aged and AD mouse models.

Methods: Brain sections of wild-type (WT) 2–3 (n=5), 6–8 (n=4), 11-12 (n=5), and 22-month mice (n=5) and 6 (n=3) and 12-month (n=4) amyloid precursor protein/presenilin 1 (APP/PS1) mice were immunostained for IBA1 to visualize microglia and skeletonized analysis was performed in FIJI. Splenic Treg populations (CD4+Foxp3+) and activation status (CD25+/-) were investigated through flow cytometry. Conventional T cells were stained with CTV and cultured with Tregs to determine Treg suppressive capacity.

Results: There was a significant increase in microglial activation in multiple brain regions with aging. Within the S1BF region, aging increased microglia density and promoted morphological changes such as decreased branch length, number, and end point voxels. Microglial staining was also increased with age in APP/PS1 mice. Aging increased Treg frequency and number in WT mice. Despite this increase, the frequency of activated CD25+Tregs was significantly decreased with age. Moreover, the proliferation index of Tregs was significantly higher in aged mice, suggesting a diminished suppressive response.

Conclusion: Age is associated with neuroinflammation. Here we show that while Tregs increase with age, the CD25+ activated subset decreases and their suppressive capacity is hampered, suggesting aging diminishes the functional capacity of Tregs.