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Enhancing protein O-GlcNAcylation in down syndrome mice mitigates memory dysfunctions through the rescue of mitochondrial bioenergetics, stress responses and pathological markers
Lanzillotta C, Prestia F, Greco V, Iavarone F, Cordella F, Sette C, Forte E, Tramutola A et al.. Redox biology, 2025-07-16
Topic: Brain proteins, microglia and lab models
Disturbances of the single sugar modification of proteins, O-GlcNAc, have been identified as a potential connection between disrupted brain metabolism and intellectual decay. In Alzheimer disease (AD), the reduced uptake of glucose in the brain results in aberrant O-GlcNAc cycling contributing to redox imbalance and neurodegeneration. Notably, alterations of O-GlcNAc homeostasis, associated with impaired O-GlcNAc transferase (OGT)/O-GlcNAcase (OGA) regulation, foster neuropathological mechanisms characterized by the presence of AD hallmarks in Down syndrome (DS) models. In the present study we examined the ability of Thiamet G (TMG), a well-known OGA inhibitor, in improving bio-energetic processes, inducing stress responses, reducing AD-related signatures and ameliorating cognition in a murine model of DS. Our data demonstrate that short-term intranasal administration of TMG restored OGA activity and normalized the global O-GlcNAc profile in mouse cortices. By a proteomic approach we identified protein components whose increased O-GlcNAc levels rescue, resulted to brain molecular and cognitive improvements. Remarkably, these included elements involved in energy production, neuronal architecture, antioxidant and stress response mechanisms. The ability of TMG in rescuing O-GlcNAc cycle and metabolic changes, associated with improved mitochondrial activity in cortical tissue, was further accompanied by changes in the O-GlcNAc/phospho ratio of APP and Tau. Functional improvements translated in enhanced recognition memory in Ts2Cje mice. Our study highlights the pivotal role of altered protein O-GlcNAcylation in DS neuropathology and establishes the molecular basis to envision the O-GlcNAc process as a promising therapeutic target to mitigate genetic- and metabolism-driven brain alterations linked to redox imbalance, mitochondrial failure and the development of AD features.
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APA 7th
Lanzillotta, C., Prestia, F., Greco, V., Iavarone, F., Cordella, F., Sette, C., et al. (2025). Enhancing protein O-GlcNAcylation in down syndrome mice mitigates memory dysfunctions through the rescue of mitochondrial bioenergetics, stress responses and pathological markers. Redox biology. https://doi.org/10.1016/j.redox.2025.103769
Vancouver
Lanzillotta C, Prestia F, Greco V, Iavarone F, Cordella F, Sette C, et al. Enhancing protein O-GlcNAcylation in down syndrome mice mitigates memory dysfunctions through the rescue of mitochondrial bioenergetics, stress responses and pathological markers. Redox biology. 2025. doi:10.1016/j.redox.2025.103769. PMID: 40684658.
BibTeX
@article{lanzillotta2025-40684658,
author = {Lanzillotta, C. and Prestia, F. and Greco, V. and Iavarone, F. and Cordella, F. and Sette, C. and Forte, E. and Tramutola, A. and others},
title = {{Enhancing protein O-GlcNAcylation in down syndrome mice mitigates memory dysfunctions through the rescue of mitochondrial bioenergetics, stress responses and pathological markers}},
journal = {Redox biology},
year = {2025},
doi = {10.1016/j.redox.2025.103769},
pmid = {40684658},
url = {https://doi.org/10.1016/j.redox.2025.103769}
}
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Key findings
- In Alzheimer disease (AD), the reduced uptake of glucose in the brain results in aberrant O-GlcNAc cycling contributing to redox imbalance and neurodegeneration.
- Notably, alterations of O-GlcNAc homeostasis, associated with impaired O-GlcNAc transferase (OGT)/O-GlcNAcase (OGA) regulation, foster neuropathological mechanisms characterized by the presence of AD hallmarks in Down syndrome (DS) models.
- The ability of TMG in rescuing O-GlcNAc cycle and metabolic changes, associated with improved mitochondrial activity in cortical tissue, was further accompanied by changes in the O-GlcNAc/phospho ratio of APP and Tau.
Why it matters
In a mouse model of Down syndrome, short-term intranasal Thiamet G normalized the O-GlcNAc profile and was linked to improved mitochondrial activity and cognition. This is animal research, so it does not yet show whether the same treatment would work or be safe in people.
Study details
- Evidence strengthLow
How this study scored 42/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Redox biology) |
| Journal's citation record | 2 / 4 | Redox Biology: journal h-index 209 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 10 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 1 / 4 | Cited 10 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Fabio Di Domenico: h-index 57 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Sapienza University of Rome: institution h-index 1,145 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40684658) |
| Free to read | 2 / 2 | Free to read |
| Total | 42 / 100 | — |
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