Mitochondria-Nuclear Communication via Lactylation in Alzheimer’s Disease

In response to RFA-AG-25-026, “Investigating Mitochondrial-Nuclear Communication in AD/ADRD,” we propose to investigate the overarching hypothesis that mitochondrial dysfunction in AD leads to increased glycolysis and elevated lactate production, which induces lactylation of histones and non-histone proteins. This post- translational modification (PTM), which conjugates lactyl groups to lysine residues on histones and proteins, results in structural and functional nuclear damage, epigenetic alterations, and dysregulation of gene expression in AD pathogenesis. We propose the following Specific Aims: 1) Investigate the effects of non-histone protein lactylation on nuclear structure and functions through tau. 2) Investigate epigenetic changes through histone lactylation in AD. 3) Characterize the effects of AD-patient-derived mitochondrial dysfunction in inducing both histone and non-histone protein lactylation through increased glycolysis. Upon completion, this study is expected to establish novel diagnostic and therapeutic targets against AD by focusing on lactylated histone and non- histone protein proteins, an area that has yet to receive NIH support. Project Number: 1R01AG096039-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Ning Wang (+1 co-PI) | Institution: UNIVERSITY OF KANSAS MEDICAL CENTER, KANSAS CITY, KS | Award Amount: $555,501 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BN-A (50)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11228985