Dr. Andrew D. R. Brown is a neuroscientist at Cardiff University, School of Biosciences, whose research centers on the mechanistic relationship between protein O-GlcNAcylation and phosphorylation on tau protein, and how their imbalance contributes to neurodegeneration in Alzheimer's disease and related tauopathies.
| Attribute | Details |
|---|---|
| Current Position | Senior Research Fellow |
| Institution | Cardiff University, School of Biosciences |
| Location | Cardiff, Wales, UK |
| Research Focus | Tau O-GlcNAcylation, tau phosphorylation, post-translational modification balance, neurodegeneration |
Education and Training:
Dr. Brown's research centers on the concept that O-GlcNAcylation and phosphorylation on tau protein exist in a dynamic "yin-yang" relationship, where they compete for the same or adjacent serine/threonine residues and mutually regulate each other's functional consequences[1][2].
Foundational framework: O-GlcNAcylation and phosphorylation compete for overlapping sites on tau. The same residues can be modified by either modification depending on cellular context. While phosphorylation promotes tau aggregation and microtubule destabilization, O-GlcNAcylation stabilizes tau in a less pathological conformation[1:1].
Site-specific mapping: Mass spectrometry studies have mapped O-GlcNAcylation sites on tau protein, identifying residues in the microtubule-binding repeat domain that are also targets for disease-relevant phosphorylation:
Dr. Brown's work supports the hypothesis that increasing O-GlcNAcylation through OGA inhibition can protect against tau pathology[3][4].
Evidence for neuroprotection: Experimental work has demonstrated that:
Age-related decline: Multiple mechanisms contribute to reduced O-GlcNAcylation in the aging brain[8][9]:
The O-GlcNAcylation deficit creates a therapeutic window where OGA inhibitors can restore tau protection[11].
Key therapeutic approaches:
Smet-Nocca C, et al. Identification of O-GlcNAc sites within peptides of the Tau protein and their impact on phosphorylation. Journal of Molecular Biology. 2011. ↩︎ ↩︎ ↩︎ ↩︎
Wani WY, et al. O-GlcNAcylation and neurodegeneration. Biochemical and Biophysical Research Communications. 2016. ↩︎ ↩︎
Wang XH, et al. MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy. Journal of Pharmacology and Experimental Therapeutics. 2018. ↩︎ ↩︎ ↩︎ ↩︎
Pan DM, et al. Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice. ACS Chemical Neuroscience. 2021. ↩︎ ↩︎ ↩︎ ↩︎
Yu Y, et al. Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation. ACS Chemical Neuroscience. 2012. ↩︎ ↩︎
Rostgaard N, et al. Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice. Molecular Neurobiology. 2023. ↩︎ ↩︎ ↩︎
Lu S, et al. SIRT1 regulates O-GlcNAcylation of tau through OGT. Aging Cell. 2020. ↩︎ ↩︎ ↩︎
Park J, et al. O-GlcNAcylation as a Therapeutic Target for Alzheimer's Disease. Biochemical and Biophysical Research Communications. 2018. ↩︎ ↩︎
Pinho TS, et al. O-GlcNAcylation and neuronal energy status: Implications for Alzheimer's disease. Frontiers in Aging Neuroscience. 2018. ↩︎ ↩︎
Katai E, et al. Oxidative stress induces transient O-GlcNAc elevation and tau dephosphorylation in SH-SY5Y cells. Cellular and Molecular Neurobiology. 2016. ↩︎ ↩︎
Pratt MR, et al. Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases. ACS Chemical Biology. 2023. ↩︎ ↩︎ ↩︎
Xia L, et al. Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice. Aging Cell. 2024. ↩︎ ↩︎ ↩︎