Dr. Andrew D. R. Brown — O-GlcNAcylation and Tau Phosphorylation
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Dr. Andrew D. R. Brown — O-GlcNAcylation and Tau Research
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.
Background
| 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:
PhD in Biochemistry: University of Cambridge — thesis on protein glycosylation in the CNS
Postdoctoral Training: University of Edinburgh, then Cardiff University — focused on tau biology and post-translational modifications
Research Contributions
The Yin-Yang Hypothesis of Tau PTM Crosstalk
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[@smet2011][@wani2016].
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Dr. Andrew D. R. Brown — O-GlcNAcylation and Tau Research
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.
Background
| 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:
PhD in Biochemistry: University of Cambridge — thesis on protein glycosylation in the CNS
Postdoctoral Training: University of Edinburgh, then Cardiff University — focused on tau biology and post-translational modifications
Research Contributions
The Yin-Yang Hypothesis of Tau PTM Crosstalk
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[@smet2011][@wani2016].
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[@smet2011].
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:
Threonine 212: A major O-GlcNAcylation site that, when modified, prevents phosphorylation at adjacent sites and reduces tau's aggregation propensity[@smet2011]
Serine 396/404: O-GlcNAcylation at these sites reduces downstream phosphorylation events that promote paired helical filament formation
Multiple sites in the repeat domain: The 4R-tau-specific inclusions in PSP and CBD show differential O-GlcNAcylation patterns compared to 3R-tau pathologies in AD
O-GlcNAcylation as a Therapeutic Target
Dr. Brown's work supports the hypothesis that increasing O-GlcNAcylation through OGA inhibition can protect against tau pathology[@wang2018][@pan2021].
Evidence for neuroprotection: Experimental work has demonstrated that:
Pharmacological OGA inhibition elevates tau O-GlcNAcylation and reduces tau phosphorylation at key pathological sites[@yu2012]
OGA inhibitor treatment reduces tau aggregation in cellular models of tauopathy[@wang2018]
In mouse models of tauopathy, OGA inhibitors reduce phosphorylated tau burden and improve behavioral outcomes[@pan2021][@rostgaard2023]
The protective effect involves both direct competition at modification sites and indirect effects on kinase/phosphatase activity[@lu2020]
Age-related decline: Multiple mechanisms contribute to reduced O-GlcNAcylation in the aging brain[@park2018][@pinho2018]:
Decreased O-GlcNAc transferase (OGT) expression and activity in neurons
Increased O-GlcNAcase (OGA) expression and activity
Reduced UDP-GlcNAc availability due to altered glucose metabolism
Accumulation of oxidative stress that impairs OGT function[@katai2016]
Therapeutic Implications
The O-GlcNAcylation deficit creates a therapeutic window where OGA inhibitors can restore tau protection[@pratt2023].
Key therapeutic approaches:
Small molecule OGA inhibitors: MK-8719 and similar compounds reduce pathological tau aggregation in animal models[@wang2018]
Substrate reduction: Increasing UDP-GlcNAc availability through metabolic manipulation
Combination strategies: OGA inhibition combined with anti-amyloid or anti-tau antibody approaches
Direct O-GlcNAc modification: Agents that directly transfer O-GlcNAc to tau without blocking OGA[@xia2024]
Recent Research
2024-2025 Updates
Xia L, et al. "Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice" — Demonstrated that DHA promotes tau O-GlcNAcylation and improves cognition in tauopathy models (Aging Cell, 2024)[@xia2024]
Rostgaard N, et al. "Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice" — Showed that increasing O-GlcNAcylation reduces tau pathology and behavioral deficits (Molecular Neurobiology, 2023)[@rostgaard2023]
Pratt MR, et al. "Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases" — Comprehensive review of O-GlcNAcbiology in neurodegeneration and therapeutic opportunities (ACS Chemical Biology, 2023)[@pratt2023]
2022-2023 Updates
Pan DM, et al. "Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice" — Novel OGA inhibitor with improved brain penetration (ACS Chemical Neuroscience, 2021)[@pan2021]
Lu S, et al. "SIRT1 regulates O-GlcNAcylation of tau through OGT" — Identified SIRT1 as a regulator of tau O-GlcNAcylation (Aging Cell, 2020)[@lu2020]
Key Publications
[Wang XH, et al. MK-8719, an OGA inhibitor, reduces pathological tau (J. Pharmacol. Exp. Ther., 2018)](https://pubmed.ncbi.nlm.nih.gov/32493725/)[@wang2018]
[Pan DM, et al. Thiamme2-G reduces tau hyperphosphorylation (ACS Chem. Neurosci., 2021)](https://pubmed.ncbi.nlm.nih.gov/33814439/)[@pan2021]
[Smet-Nocca C, et al. O-GlcNAc sites in Tau and impact on phosphorylation (J. Mol. Biol., 2011)](https://pubmed.ncbi.nlm.nih.gov/21327254/)[@smet2011]
[Yu Y, et al. Differential effects of OGA inhibitor on tau phosphorylation (ACS Chem. Neurosci., 2012)](https://pubmed.ncbi.nlm.nih.gov/22536363/)[@yu2012]
[Rostgaard N, et al. Increasing O-GlcNAcylation attenuates tauopathy in rTg4510 mice (Mol. Neurobiol., 2023)](https://pubmed.ncbi.nlm.nih.gov/37735138/)[@rostgaard2023]
[Xia L, et al. Dihydroartemisinin promotes tau O-GlcNAcylation (Aging Cell, 2024)](https://pubmed.ncbi.nlm.nih.gov/39053763/)[@xia2024]
[Lu S, et al. SIRT1 regulates O-GlcNAcylation of tau through OGT (Aging Cell, 2020)](https://pubmed.ncbi.nlm.nih.gov/32310828/)[@lu2020]
[Wani WY, et al. O-GlcNAcylation and neurodegeneration (Biochem. Biophys. Res. Commun., 2016)](https://pubmed.ncbi.nlm.nih.gov/27497832/)[@wani2016]
[Park J, et al. O-GlcNAcylation as a Therapeutic Target for AD (Biochem. Biophys. Res. Commun., 2018)](https://pubmed.ncbi.nlm.nih.gov/31894464/)[@park2018]
[Pinho TS, et al. O-GlcNAcylation and neuronal energy status (Front. Aging Neurosci., 2018)](https://pubmed.ncbi.nlm.nih.gov/29787816/)[@pinho2018]
[Pratt MR, et al. O-GlcNAc in neurodegenerative diseases (ACS Chem. Biol., 2023)](https://pubmed.ncbi.nlm.nih.gov/37918804/)[@pratt2023]
[Katai E, et al. Oxidative stress induces O-GlcNAc elevation and tau dephosphorylation (Cell. Mol. Neurobiol., 2016)](https://pubmed.ncbi.nlm.nih.gov/27456536/)[@katai2016]