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Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome
Lanzillotta C, Tramutola A, Di Giacomo G, Marini F, Butterfield DA, Di Domenico F, Perluigi M, Barone E.. Free radical biology & medicine, 2021-01-29
Topic: Brain proteins, microglia and lab models
Dysregulation of brain insulin signaling with reduced downstream neuronal survival and plasticity mechanisms are fundamental abnormalities observed in Alzheimer disease (AD). This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the inhibition of IRS1. Since Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration in DS and whether they contribute to early onset AD in DS. We evaluated levels and activation of proteins belonging to the insulin signaling pathway (IR, IRS1, BVR-A, MAPK, PTEN, Akt, GSK3β, PKCζ, AS160, GLUT4) in the frontal cortex of Ts65dn (DS model) (n = 5-6/group) and euploid mice (n = 6/group) at different ages (1, 3, 9 and 18 months). Furthermore, we analyzed whether changes of brain insulin signaling were associated with alterations of: (i) proteins regulating brain energy metabolism (mitochondrial complexes, hexokinase-II, Sirt1); (ii) oxidative stress (OS) markers (iii) APP cleavage; and (iv) proteins mediating synaptic plasticity mechanisms (PSD95, syntaxin-1 and BDNF). Ts65dn mice showed an overall impairment of the above-mentioned pathways, mainly characterized by defects of proteins activation state. Such alterations start early in life (at 1 month, during brain maturation). In particular, accumulation of inhibited IRS1, together with the uncoupling among the proteins downstream from IRS1 (brain insulin resistance), characterize Ts65dn mice. Furthermore, reduced levels of mitochondrial complexes and Sirt1, as well as increased indices of OS also were observed. These alterations precede the accumulation of APP-C99 in Ts65dn mice. Tellingly, oxidative stress levels were negatively associated with IR, IRS1 and AS160 activation as well as mitochondrial complexes levels in Ts65dn mice, suggesting a role for oxidative stress in the observed alterations. We propose that a close link exists among brain insulin resistance, mitochondrial defects and OS that contributes to brain dysfunctions observed in DS, likely favoring the development of AD in DS.
Key findings
- This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the inhibition of IRS1.
- Furthermore, we analyzed whether changes of brain insulin signaling were associated with alterations of: (i) proteins regulating brain energy metabolism (mitochondrial complexes, hexokinase-II, Sirt1); (ii) oxidative stress (OS) markers (iii) APP cleavage; and (iv) proteins mediating synaptic plasticity mechanisms (PSD95, syntaxin-1 and BDNF).
- Ts65dn mice showed an overall impairment of the above-mentioned pathways, mainly characterized by defects of proteins activation state.
- Tellingly, oxidative stress levels were negatively associated with IR, IRS1 and AS160 activation as well as mitochondrial complexes levels in Ts65dn mice, suggesting a role for oxidative stress in the observed alterations.
Why it matters
In a mouse model of Down syndrome, brain insulin signaling and related energy, oxidative stress, and synaptic pathways were impaired starting early in life. These are animal findings and do not test any treatment in people.
Study details
- Evidence strengthLow
How this study scored 43/100
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 (Free radical biology & medicine) |
| Journal's citation record | 3 / 4 | Free Radical Biology and Medicine: journal h-index 378 (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 | 3 / 5 | 2021 — within 6 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 | 4 / 7 | Cited 46 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.6 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 3 / 6 | Cited 6.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 5 other studies in this library |
| Still being cited | 2 / 4 | Cited 22 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Eugenio Barone: h-index 47 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Sapienza University of Rome: institution h-index 1,145 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33516914) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Lanzillotta, C., Tramutola, A., Di Giacomo, G., Marini, F., Butterfield, D. A., Di Domenico, F., et al. (2021). Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome. Free radical biology & medicine. https://doi.org/10.1016/j.freeradbiomed.2021.01.042
Vancouver
Lanzillotta C, Tramutola A, Di Giacomo G, Marini F, Butterfield DA, Di Domenico F, et al. Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome. Free radical biology & medicine. 2021. doi:10.1016/j.freeradbiomed.2021.01.042. PMID: 33516914.
BibTeX
@article{lanzillotta2021-33516914,
author = {Lanzillotta, C. and Tramutola, A. and Di Giacomo, G. and Marini, F. and Butterfield, D. A. and Di Domenico, F. and Perluigi, M. and Barone, E.},
title = {{Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome}},
journal = {Free radical biology \& medicine},
year = {2021},
doi = {10.1016/j.freeradbiomed.2021.01.042},
pmid = {33516914},
url = {https://doi.org/10.1016/j.freeradbiomed.2021.01.042}
}
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