Diminished O-GlcNAcylation in Alzheimer's disease is strongly correlated with mitochondrial anomalies
Open accessAbstract
Uncover the initial cause(s) underlying Alzheimer's disease (AD) pathology is imperative for the development of new therapeutic interventions to counteract AD-related symptomatology and neuropathology in a timely manner. The early stages of AD are characterized by a brain hypometabolic state as denoted by faulty glucose uptake and utilization and abnormal mitochondrial function and distribution which, ultimately, culminates in synaptic "starvation" and neuronal degeneration. Importantly, it was recently recognized that the post-translational modification β-N-acetylglucosamine (O-GlcNAc) modulates mitochondrial function, motility and distribution being proposed to act as a nutrient sensor that links glucose and the metabolic status to neuronal function. Using post-mortem human brain tissue, brain samples from the triple transgenic mouse model of AD (3xTg-AD) and in vitro models of AD (differentiated SH-SY5Y cells exposed to AD-mimicking conditions), the present study is aimed to clarify whether O-GlcNAcylation, the posttranslational modification of intracellular proteins by O-GlcNAc, contributes to "mitochondrial pathology" in AD and its potential as a therapeutic target. A reduction in global O-GlcNAcylation levels was observed in the brain cortex and hippocampus of AD subjects. Moreover, GlcNAcylation levels are higher in mature mice but the levels of this posttranslational modification are lower in 3xTg-AD mice when compared to control mice. The in vitro models of AD also exhibited a marked reduction in global O-GlcNAcylation levels, which was strongly correlated with hampered mitochondrial bioenergetic function, disruption of the mitochondrial network and loss of cell viability. Conversely, the pharmacological modulation of O-GlcNAcylation levels with Thiamet-G restored O-GlcNAcylation levels and cell viability in the in vitro models of AD. Overall, these results suggest that O-GlcNAcylation is involved in AD pathology functioning as a potential link between mitochondrial energetic crisis and synaptic and neuronal degeneration. This posttranslational modification represents a promising therapeutic target to tackle this devastating neurodegenerative disease.
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O-GlcNAcylation levels are reduced in the cortex and hippocampus of AD individuals and in vivo and in vitro models of AD.
“O-GlcNAcylation levels are reduced in the cortex and hippocampus of AD individuals and in vivo and in vitro models of AD [175].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [175]
Reduced O-GlcNAcylation is related to mitochondrial dysfunction and neurodegeneration.
“The reduced O-GlcNAcylation is related to mitochondrial dysfunction and neurodegeneration [175], which may be associated with neuroinflammation.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [175]
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- Authors
- Pinho, T. S., Correia, S. C., Perry, G., Ambrósio, A. F., & Moreira, P. I.
- Affiliations
- Centro de Neurociências e Biologia Celular (PT)
- The University of Texas at San Antonio (US)
- University of Coimbra (PT)
- Corresponding author
- Correia, Sónia C.
- Moreira, Paula I.
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 1865
- Issue
- 8
- Pages
- 2048-2059
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2899990272
- Cited by
- 70
- References
- 63
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 15 · 2023: 8 · 2022: 8 · 2021: 17 · 2020: 7 · 2019: 4 · 2018: 1
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação para a Ciência e a Tecnologia (SFRH/BPD/109822/2015)
- Healthy Aging 2020 (CENTRO-01-0145-FEDER-000012)
- FEDER
- FCT (PEst-C/SAU/LA0001/2013-2014, UID/NEU/04539/2013)
- Santa Casa da Misericórdia de Lisboa - Mantero Belard Award (MB-1049-2015)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, O-GlcNAcylation, mitochondrial dysfunction, mitochondrial bioenergetics, mitochondrial network, Thiamet G, 3xTg-AD mice, SH-SY5Y cells, cerebral cortex, hippocampus, glucose metabolism, synaptic degeneration, neuronal viability, therapeutic target
- MeSH terms
- Acetylglucosamine, Acylation, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cell Line, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Protein Processing, Post-Translational
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