Modulation of microglial immunometabolism by B-hydroxybutyrate in tauopathy

Active Project Grant Awarded Last action

Award ID
F31AG101925
Recipient
Awarding agency
Obligated
$43,565

Award facts

Assistance listing
93.866 Aging Research
Completion date 0% complete
Place of performance
La Jolla, CA 92093, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Alzheimer's disease (ad) remains an urgent public health crisis, affecting over 6.9 million americans with no disease-modifying treatments. Beyond hallmark amyloid and TAU pathology, ad is characterized by profound neuroimmune dysfunction, particularly microglial activation coupled with metabolic dysfunction and lipid droplet accumulation. The goal of this project is to define how Β-hydroxybutyrate (BHB), a ketone body elevated during ketogenic diet or fasting, modulates microglial immunometabolism to rescue function and mitigate tauopathy- driven neurodegeneration. The long-term goal is to uncover molecular mechanisms by which metabolism intersects with neuroinflammation, identifying novel therapeutic targets for ad and related tauopathies, in line with the NIH mission to advance treatments for devastating neurological disorders. The central hypothesis is that BHB promotes a beneficial shift in microglial metabolism through the BHB receptor HCAR2, restoring homeostatic functions compromised in tauopathy. Aim 1 will characterize how BHB modulates microglial metabolism and function in the context of tauopathy. In vitro studies will assess transcriptomic, metabolic, and functional changes in primary microglia treated with TAU fibrils and BHB, including analysis of HCAR2 conditional knockout microglia to determine receptor involvement. Aim 2 will determine how BHB influences neuron-microglia interactions in tauopathy. Effects of BHB-treated microglia on neuronal health, synaptic integrity, and TAU propagation will be evaluated using conditioned media transfer, CO- culture systems, and microfluidics-based assays. In vivo relevance will be tested using tauopathy mice with microglia-specific HCAR2 knockout on a BHB diet to assess the role of HCAR2 signaling in mediating BHB's neuroprotective effects. The fellowship training plan integrates advanced training in neuroimmunology, metabolism, RNA sequencing, and bioinformatics, alongside professional development in written and oral research communication. Guided by a multidisciplinary mentorship team and embedded within a collaborative research environment in the chen laboratory at UC SAN diego, the training plan will provide the scientific and professional foundation for an independent career at the interface of neuroscience and medicine. This research and training will contribute to a deeper mechanistic understanding of microglial metabolism and foster the development of innovative metabolic therapeutics for ad.

Quick answers

Who received award F31AG101925?

F31AG101925 was awarded to University Of California, San Diego by National Institute on Aging (National Institutes of Health) on November 26, 2026.

How much is award F31AG101925 worth?

$43,565 has been obligated on F31AG101925.

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