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Investigating the effects of increasing O-GlcNAcylation in Alzheimer's disease

Award Number: F99NS139543
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Investigating the effects of increasing O-GlcNAcylation in Alzheimer's disease - PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a devastating neurodegenerative disease with limited therapeutic options. Progressive accumulation of the pathological markers, hyperphosphorylated Tau (pTau), amyloid-beta, and gliosis begin up to 20 years before cognitive impairment occurs. Published reports from our lab and others have shown that the TgF344-AD rat model displays many of the early pathological abnormalities that occur in patients with AD, including endogenous pTau accumulation in the locus coeruleus prior to other brain regions, Aβ accumulation throughout hippocampus, degeneration of noradrenergic (NA) axons in hippocampus, reactive astrocytes and microglia, as well as a synaptic dysfunction as early as 6 months in the dentate gyrus. Therapeutic strategies that interfere with these pathological changes could slow disease progression. Increasing the post- translational modification, O-GlcNAcylation, has received recent attention, as it competes with serine/threonine phosphorylation on Tau, preventing its hyperphosphorylation and accumulation. Increasing O-GlcNAcylation also increases non-amyloidogenic processing of amyloid precursor protein due to O-GlcNAcylation of gamma secretase. Pharmacological inhibitors of O-GlcNAcase, the enzyme that removes O-GlcNAc moieties from proteins, are currently in clinical trials for the treatment of AD in patients. Using the TgF344-AD rat model and a combination of technical approaches including immunohistochemistry, confocal imaging, Western blot and brain slice electrophysiology, my dissertation research focuses on pharmacologically increasing O- GlcNAcylation in TgF344-AD rats to test whether it is therapeutically beneficial by (1) decreasing pathogenic accumulation of pTau and amyloid-β (Aβ), preventing NA axon degeneration, and decreasing astrocyte and microglia activation, (2) prevents the pathologically increased LTP due to β-ARs function at MPP-DG synapses and (3) maintaining astrocyte function, including astrocytic β-ARs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $41,828 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/28/2025	NON-COMPETING CONTINUATION	$41,828
														Subtotal = $41,828

Issue Date FY: 2024 ( Subtotal = $41,264 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/18/2024	NEW	$41,264
														Subtotal = $41,264

Grand Total All Awards = $83,092

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Investigating the effects of increasing O-GlcNAcylation in Alzheimer's disease

Award Number: F99NS139543

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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