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NIH grant 1K99AG097912-01A1: A Novel Approach to Alzheimer's: TargetingCholesterol Metabolism in the Liver and Brain
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Benjamin A Kugler. Award: $123894.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY/ABSTRACT
This K99/R00 Pathway to Independence Award supports Dr. Benjamin A. Kugler’s transition to an independent
investigator studying systemic metabolic factors contributing to Alzheimer’s disease (AD) pathogenesis. Dr.
Kugler, a postdoctoral scholar at the University of Kansas Medical Center, has expertise in mitochondrial
physiology and liver cholesterol/bile acid metabolism. This project integrates these fields to examine how
impaired brain cholesterol export and disrupted liver bile acid metabolism interact to influence brain
mitochondrial function and AD pathology. Under normal conditions, brain cholesterol is converted to 24-
hydroxycholesterol, transported to the liver, and converted to bile acids for excretion. In AD, this pathway
appears disrupted, coinciding with the accumulation of toxic oxysterols within brain mitochondria and
mitochondrial dysfunction, though the causal relationship remains unclear. The proposed studies will test
whether impaired neuronal cholesterol export and altered liver bile acid metabolism disrupt brain mitochondrial
function and accelerate AD pathology using iPSC-derived neurons and 5xFAD mouse models. Specifically, Aim
1 will determine the impact of Cyp46a1-mediated cholesterol export from the brain on neuronal mitochondrial
function and AD pathology, while Aim 2 will assess how modulation of liver bile acid metabolism influences
brain cholesterol homeostasis, cognition, and pathology. Concurrently, Dr. Kugler will receive advanced training
in AD-related mitochondrial physiology, iPSC modeling, stable-isotope and mass spectrometry approaches,
and cognitive assessment, along with professional development in leadership, laboratory management, and
research rigor under the mentorship of Drs. Heather Wilkins, John Thyfault, and Shawn Burgess. This
integrated research and training plan will provide the expertise and preliminary data necessary for Dr. Kugler to
establish an independent research program focused on the liver–brain axis in AD and develop systemic
therapeutic strategies to prevent and treat this disease.document fetched 2026-09-20 02:42