Alzheimer's disease

Dissecting modulations of glucose metabolism in Alzheimer's disease using MR metabolic imaging of hyperpolarized pyruvate

Metabolic changes are prominent in Alzheimer's disease and occur early in the disease process. However, why these metabolic changes happen and how they contribute to disease pathophysiology is poorly understood.  but they remain poorly understood. In this research direction, we investigate how the metabolic flux through key steps in glucose metabolism is disrupted by central AD proteins (amyloid precursor protein (APP), tau and apoE4), and to determine if these steps are effective biomarkers for early disease that can be detected with hyperpolarized 13C MRSI. To do so, we have access to  several animal models that we monitor using in vivo metabolic imaging: 1. APP (hAPP-J20 transgenic mice with mutant human APP (Swedish and Indiana mutations), hAPP knock-in mice with the Swedish, Beyreuther/Iberian and Arctic mutations (hAPPNL-G-F KI), and wildtype mice), 2. human tau (A152T-variant human tau (hTau-A152T) that increases the risk of AD and other tauopathies, hTau-WT and wild-type mice) and 3. apoE4 (apoE4 KI, apoE3 KI and wild-type mice). We investigate live brain slices from all mice models using a MR-compatible perfusion system. We have the capability to perform these experiments using HP 13C and conventional 13C  MR on a 11.7Tesla in the UCSF Biomedical NMR lab. Unlike in vivo, this platform supports studying metabolic fluxes over many hours.

On this project, we work closely with our great colleague Prof. Ken Nakamura, MD, Ph.D., whose lab investigates how disruptions of mitochondria—the “power centers” of cells that convert nutrients into energy—contribute to the development and progression of Parkinson’s disease and Alzheimer’s disease.