PROJECT SUMMARY/ABSTRACT
Lipids make up half of the brain’s weight and are required for the proper development, structure, and
function of healthy brains. As we age, the risk of cognitive decline and neurodegenerative diseases increases.
This proposal seeks to understand whether aging changes the lipid composition of the brain and whether these
changes contribute to aging and/or predispose us to disease. Unfortunately, the field currently lacks a deep
understanding of lipid composition and dynamics in the aging brain, preventing progress toward this larger goal.
Using a unique approach to lipidomics that integrates chemistry to examine the brain lipidome of aging mice led
to the discovery of the unannotated 3-sulfo galactosyl diacylglycerol (SGDG) lipids as the most significantly
decreased lipids in the aging brain. Furthermore, SGDGs are a novel class of anti-inflammatory lipids, suggesting
that decreased SGDG levels with aging may promote brain inflammation.
The discovery of SGDGs as age-regulated lipids represent a new frontier at the interface of aging
research and lipid biology. This proposal seeks to answer the most pressing questions about SGDGs and their
role in aging and disease. Specifically, this proposal asks how SGDG levels are controlled during aging and
neurodegenerative disease (Aim 1); determine whether SGDGs are bioactive in vivo and whether they reverse
inflammation or any other age- or disease-associated phenotypes (Aim 2); and measure SGDG distribution in
the brain and myelin of mouse models of aging and neurogenerative disease (Aim 3). To accomplish these goals,
the approach relies heavily on chemistry to synthesize of SGDGs and SGDG analogs and use these unique
reagents for cell biology, in vivo pharmacology and biology, proteomics, genomics, and imaging methods to
elucidate SGDG’s role in aging and neurodegenerative disease.
These studies will explain how age-related differences in lipids and lipid metabolism can contribute to
aging and neurodegenerative disease. Furthermore, since SGDGs are also found in human and primate brains,
this information may contribute to the longer-term goal of knowing which age-regulated changes in lipids and
lipid metabolism predispose humans to cognitive decline and neurodegeneration.