P026 - REGULATION OF DEPRESSION-LIKE BEHAVIOR VIA FOXP3+ T CELL-MEDIATED IMMUNOMODULATION: A CAUSAL LINK TO ALZHEIMER’S DISEASE PATHOPHYSIOLOGY (ID 1233)

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Abstract

Aims

Alzheimer's disease (AD) is the most common of dementia among the elderly. Among various causative factors, depression has emerged as a critical factor, increasing the risk of developing AD by 2-4-fold. Thus, elucidating underlying molecular mechanisms linking depression to AD would offer feasible target for preventing AD progression. We have reported the involvement of Forkhead box P3 (FOXP3) modulating the function of regulatory T cells in peripheral immune system, inducing depression-like behavior in mice following stress. However, it is not known if alleviating depression by modulating FOXP3 could reduce the risk of developing AD-like pathologies.

Methods

In the present study, we utilized a FOXP3 or FOXP3x5xFAD mice by treating with diptheria toxin, which causes a reduction of FOXP3 expression. To evaulate anxitey, depression-like behaviors and cognitive impairments, light/dark transition, forced swimming and Y-maze test were perfromed, respectively. We analysed intestinal immune response using immunohistochemistry and examined molecular changes in hippocampus using RNAseq.

Results

We observed depression, anxiety-like behavior following downregulation of FOXP3. Furthermore, recovery of FOXP3 expression attenuated these behavioral change, accompanied by a significant alteration of Treg/Th17 ratio. To examine the relevance of this mechanism in AD, We are investigating whether reduction of FOXP3 in AD changes intestinal immune response and depletion of peripheral FOXP3 expression alters blood brain barrier permeability leading to neuroinflammation and thereby exacerbating brain cognitive behaviors.

Conclusions

Thus our data suggest FOXP3 as a causal link in the peripheral immune system mediating depression like behavior, leading to exacerbation of AD type brain cognitive deterioration. (Supported by the Altschul Foundation)

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