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2017 Grants - Pahan
PPARalpha in APP Metabolism
Kalipada Pahan, Ph.D.
Rush University Medical Center
2017 Zenith Fellows Award Program
Can novel factors produced in the brain help prevent the formation of toxic beta-amyloid?
One of the hallmarks of Alzheimer’s disease is the accumulation of beta-amyloid protein fragments into plaques inside the brain. Beta-amyloid protein fragments are formed from the processing of its parent protein called amyloid precursor protein (APP). However, APP can be metabolized by alternative processes that do not allow the formation of beta-amyloid. It is possible that stimulating this “non-amyloid” pathway could help prevent the build-up toxic beta-amyloid in the brain.
In previous studies, Kalipada Pahan, Ph.D., and colleagues have found that activation of a protein called peroxisome proliferator-activated receptor (PPAR) appears to control the processing of APP in nerve cells. More research is needed to better understand these mechanisms and identify new ways to regulate APP non-amyloidogenic processing as a potential way to slow or prevent beta-amyloid accumulation in the brain during Alzheimer’s disease.
Dr. Pahan and team have recently identified three novel compounds that are found in high levels in the healthy brain, specifically in a region called the hippocampus which is important for memory function. These novel compounds can activate PPAR which could help shift APP to be processed down the non-amyloid pathway. For their current studies, the researchers will administer these novel compounds to Alzheimer’s-like mice and determine if they can effectively lower levels of beta-amyloid in the brain.
Results from this study could improve our understanding of the fundamental mechanisms involved in the processing of APP and the formation of beta-amyloid. Importantly, these findings may identify novel compounds that prevent the build-up of beta-amyloid in the brain and could potentially be developed as treatments to slow, halt or prevent the progression of Alzheimer’s disease.