Oxysterols in Innate and Adaptive Immunity in a Tauopathy Mouse Model

This project aims to clarify the role of brain cholesterol metabolites (oxysterols) in lymphocyte infiltration into the brain to promote neurodegeneration mediated by tau pathology.

Neuronal loss in Alzheimer’s disease is linked to brain infiltration of blood-derived immune cells in a neurotoxic cascade of tau protein accumulation and inflammation in the brain. Preliminary studies show evidence for altered brain cholesterol metabolism in mediating tau pathology and infiltration of blood immune cells into the brain. This project aims to investigate this pathway with the long-term goal of pharmacological intervention to block neuronal loss in Alzheimer’s.

Recent discoveries have highlighted an interplay between lipid metabolism and neuroinflammation in neurodegeneration. Cholesterol metabolized into oxysterols modulate the immune response, but are poorly understood in the context of AD. The innovation in the proposed research stems from the discovery of a novel pathogenic role for an oxysterol signaling pathway potentially activated by early impairments in cholesterol metabolism intersecting with the activation of innate and adaptive immune response in AD pathogenesis.

Once the study is complete, we will be able to determine how enzymatic conversion of cholesterol into 25HC by the enzyme cholesterol 25-hydroxylase (Ch25h) and/or its subsequent metabolite, 7?,25-diHC regulates both innate and adaptive immunity in the context of neurodegeneration mediated by tau pathology in a sex-dependent manner. The immediate benefit from our results will test whether pharmacological inhibition of Ch25h or antagonism of the Gpr183 receptor may offer a novel therapeutic strategy to modulate neurodegeneration in AD and related dementias.