Bioenergetic contributions to TAU phosphorylation in aging and alzheimer disease

The National Institute on Aging, part of the Department of Health and Human Services National Institutes of Health, awarded $154,960 to the University of Kansas Medical Center Research Institute, Inc. on February 26, 2026, under the Aging Research program (CFDA 93.866).

The recipient will conduct research combining cellular and clinical measures to examine bioenergetic contributions to tau phosphorylation in aging and Alzheimer's disease. The work leverages existing clinical data from the KU Alzheimer's Disease Research Center and integrates it with cellular experiments using the cytoplasmic hybrid neuronal cell model. The research addresses the mechanism by which impaired mitochondrial bioenergetics may contribute to microtubule depolymerization and tau phosphorylation, pathological hallmarks of Alzheimer's disease that track closely with clinical cognitive impairment.

Performance occurs in Kansas City, Kansas, with an ultimate completion date of August 13, 2028. The Aging Research program supports biomedical, social, and behavioral research and training directed toward understanding the aging process and diseases affecting older adults, with particular emphasis on Alzheimer's disease and related dementias.

Abstract

Alzheimer's disease (ad) is the most common form of dementia and affects nearly 6.9 million older adults in the united states. IT is pathologically defined by accumulation of amyloid plaques and neurofibrillary TAU tangles (nfts) within the brain, leading to cytotoxicity and neurodegeneration. The progression of these biomarkers begins nearly a decade before onset of cognitive impairment. While many factors contribute to ad development, a significant risk for ad that can begin early in life includes metabolic impairment and mitochondrial dysfunction. Mitochondrial dysfunction has been observed in many different models of ad, but the mechanism of its contribution to ad is still unclear. In ad, TAU protein is hyperphosphorylated and aggregates into nfts that regionally deposit throughout the brain; TAU deposition tracks very closely with clinical manifestation of cognitive impairment in ad patients - this emphasizes the importance of understanding the mechanisms that drive TAU phosphorylation, which are still unclear. TAU is a microtubule-associated protein and is essential for microtubule stability within the axons of neurons; when neurodegeneration occurs in ad, microtubules depolymerize, TAU is phosphorylated, and subsequently aggregates. Microtubule stability is an energy-dependent process. Impaired mitochondrial bioenergetics, as have been seen in ad, might contribute to microtubule depolymerization by altering the amount of bioavailable cellular energy, leading to neurodegeneration and TAU phosphorylation. We seek to address this knowledge GAP by combining cellular and clinical measures from clinical research participants in our KU alzheimer's disease research center. We will leverage existing clinical data from our studies and combine IT with cellular experiments using the cytoplasmic hybrid (cybrid) neuronal cell model, which come from the same research participants. Cybrid cell lines are generated using mitochondrial DNA (mtdna) from our research participants, allowing US to probe specific questions regarding the impact of mitochondrial metabolism on cellular function. To investigate the impact of mitochondrial bioenergetics on TAU phosphorylation, we will use cybrid lines from individuals with and without ad to evaluate differences in cybrid proteomes and mitochondrial function (aim 1A) and alterations in mtdna that might contribute to ad development (AIM1B). Combined, aims 1A and 1B will provide critical knowledge regarding the mechanism behind TAU phosphorylation in ad, and how mtdna and mitochondrial function contribute to these observations. We will then investigate relationships between mitochondrial bioenergetics and clinically relevant measures impacted by ad, such as neuroimaging and cognition (aim 2). This proposal will investigate the role of mitochondrial bioenergetics in TAU phosphorylation in ad and aging, and provides a training plan that will support the applicant in developing essential skills for a future career as a translational researcher in academia.