Research investigates brain energy metabolism at the intersection of aging and Alzheimer's disease
A new five-year, $3.5 million research study funded by the National Institutes of Health will allow scientists to investigate how changes in a key metabolic process contributes to aging biology and Alzheimer's disease. Researchers hope that the work will lead to new strategies to combat the cognitive decline that accompanies aging and the neuropathology that characterizes Alzheimer's disease.
Rozalyn Anderson, PhD (pictured at upper right), associate professor, and Luigi Puglielli, MD, PhD (pictured above and at lower right), professor, both of Geriatrics and Gerontology, have been awarded funding for a proposal entitled, "Acetyl-CoA flux and mitochondrial adaptation: a pathogenic role in aging and Alzheimer's Disease?"
The primary objective of the effort is to dissect the molecular aspects of brain metabolism as a function of age and Alzheimer's disease.
Previous investigations by the research teams found that a protein quality control process in cells is also directly involved in the neurobiology of aging and progression of Alzheimer's disease. The process involves transfer of newly-made proteins from the cytosol to a compartment of the cell called the endoplasmic reticulum (ER) followed by attachment of an acetyl group to the proteins. In mouse studies, tinkering with this process by changing the amount of available acetyl-Coenzyme A (which is the source of acetyl groups) or inhibiting protein acetylation in the ER affected neuropathology of aging and Alzheimer's disease.
The new study will probe how the cytosol-to-ER flux of acetyl-CoA regulates biochemical processes in the brain that are devoted to energy metabolism. The work will use techniques including high-resolution proteomics in mice and primates, brain tissue, and induced pluripotent stem cell (iPSC)-derived human neurons. Additional laboratory studies will focus on specific metabolic and molecular events governing aging and Alzheimer's disease.
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