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NIH grant 1K99AG103522-01: Bioenergetic Reprogramming through Ketogenic Enzymes: A Mitochondrial Strategy for Alzheimer's Disease
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Taylor J. Kelty. Award: $138121.
Start: 2026-09-11T00:00:00.
ABSTRACT
Alzheimer’s disease (AD) affects nearly 7 million people in the United States. Glucose hypometabolism, impaired
tricarboxylic acid (TCA) cycle activity, and reduced oxidative phosphorylation are observed with aging and
exacerbated in AD. These energy deficits can lead to decreased nicotinamide adenine dinucleotide (NAD⁺)
recycling that contributes to reduced sirtuin 1 (SIRT1) activity, disrupted mitochondrial bioenergetics, and
cognitive decline. Ketones can cross the blood–brain barrier to provide an alternative energy source, preserve
NAD⁺ levels, and enhance SIRT1 activity. Although ketone supplementation shows therapeutic potential in AD
patients and 5x familial Alzheimer’s disease (5xFAD) mice, ketone utilization in AD brains is less robust,
suggesting dysregulation of hepatic ketogenesis via 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or
neuronal ketolysis via 3-oxoacid CoA-transferase 1 (Oxct1). We have shown that hepatic HMGCS2 knockdown
impairs brain mitochondrial function, cognition, and synaptic plasticity in rats, and preliminary data in 5xFAD mice
reveal that HMGCS2 knockdown exacerbates cognitive decline and amyloidosis while reducing cortical
mitochondrial content and biogenesis. Additionally, we show significantly reduced OXCT1 protein in post-mortem
AD brains compared to those with frontotemporal dementia, revealing OXCT1 as a potential disease-specific
metabolic vulnerability in AD. Neuronal Oxct1 overexpression also decreased β-amyloid burden and enhanced
mitochondrial biogenesis in 5xFAD mice and decreased β-amyloid burden in AD-derived cerebral organoids.
Thus, I will test the hypothesis that enhanced ketone metabolism restores mitochondrial bioenergetics and
metabolite availability to mitigate AD progression. In Aim 1 (K99 phase), hepatocyte-targeted adeno associated
viral (AAV) knockdown of HMGCS2 in aged 5xFAD mice, combined with studies in induced pluripotent stem cell
(iPSC)-derived neurons from AD patients treated with ketones or NAD+ (for SIRT1 activation) with/without SIRT1
inhibitors, will test whether impaired hepatic ketogenesis accelerates AD by reducing brain ketone supply and
disrupting NAD⁺/SIRT1 signaling. In Aim 2 (R00 phase), neuron-specific AAV knockdown or overexpression of
Oxct1 in aged 5xFAD mice, together with Oxct1 manipulation in iPSC neurons with or without SIRT1 inhibitors
or metabolic supplements, will test whether neuronal ketolysis regulates amyloidogenic processing by promoting
bioenergetic metabolite availability. These innovative studies will mechanistically assess if modulating either
hepatic or neuronal ketone metabolism can restore energy metabolites to protect against AD-related pathological
burden. The K99 phase will provide advanced training in AD and aging neuropathological assessment, iPSC-
derived neuronal modeling, liver- and brain-targeted AAV interventions, mitochondrial bioenergetics, and
metabolomic analyses supporting the establishment of an independent research program in the R00 phase.document fetched 2026-09-20 02:42