Jianhua Zhang, Ph.D.Jianhua Zhang, Ph.D., a professor in the Division of Molecular and Cellular Pathology, recently received a Heersink School of Medicine Bridge Funding Award. This program aims to improve the success of research faculty experiencing gaps in funding by providing continuing research support.
The project, titled “Targeting metabolic regulation in Alzheimer’s disease” centers on the growing recognition that impaired glucose metabolism and disruptions in mitochondrial function emerge early in Alzheimer’s disease and help drive its progression.
For decades, therapeutic strategies have largely focused on two hallmark features of the disease, amyloid plaques, and tau tangles. Amyloid plaques are clumps of misfolded proteins that form in the spaces between nerve cells, leading to problems with brain function. Tau tangles are abnormal, twisted aggregates of tau protein that accumulate inside neurons, causing malfunction and cell death. Patient experience with FDA-approved amyloid targeting drugs has highlighted important limitations and side effects, emphasizing the need for new therapeutic directions.
Using in vivo PET scan imagining, Zhang and her team found that blocking ROCK1/2 proteins, which are enzymes that regulate cell shape, movement, and cytoskeletal stability, improved how the brain uses glucose and supports healthier communication between neurons. The same treatment decreased brain inflammation, lowered harmful tau phosphorylation, and suppressed the abnormal elevation of a key glycolytic enzyme in PS19 tau transgenic mice.
‘We have found that a specific brain-permeable ROCK1/2 inhibitor reduced ptau species and enhanced mitochondrial bioenergetics in neural stem cells,” Zhang said. “In the proposed study, we will leverage our expertise with in vivo PET imaging for longitudinal studies to determine the impact of ROCK inhibition on glucose metabolism, mitochondrial electron transport chain activity, and synaptic density.”
The team will also define the pharmacokinetics of the ROCK inhibitor and evaluate its effects across both tau and amyloid based Alzheimer’s mouse models. Completion of this work may reveal a new therapeutic avenue for Alzheimer’s disease and provide deeper insight into the metabolic disruptions that contribute to its development.