Cerebellar nuclei remain vulnerable to cuprizone-induced demyelination in adult and aged mice: A longitudinal multimodal MRI-histology study
- 1Neurosciences, Novartis Biomedical Research, CH-4056 Basel, Switzerland
- 2Diseases of Aging and Regenerative Medicine, Novartis Biomedical Research, CH-4056 Basel, Switzerland
Abstract
Age is a major determinant of demyelination and remyelination capacity. Here, we investigated age-dependent brain responses to acute cuprizone exposure in female C57BL/6 mice using longitudinal multimodal Magnetic resonance imaging (MRI) and histological analyses. Our aim was to determine whether any brain region in very old animals remains susceptible to cuprizone-induced pathology. Adult (6-month-old) and aged (18-month-old) mice received 0.2% cuprizone in the diet for 5 weeks, followed by 4 weeks of recovery on normal chow, with in vivo MRI performed at baseline, during intoxication, and throughout recovery. Magnetization transfer ratio (MTR) and T2-weighted signal were used as MRI surrogates of myelin integrity and neuroinflammation, respectively, whereas T1-weighted signal was assessed as a potential marker sensitive to oxidative stress. In adult mice, cuprizone induced robust and region-specific pathology, including reduced MTR and increased T2-weighted signal in the corpus callosum, accompanied by microgliosis, astrocytosis, and increased APP-positive dystrophic neurites. These abnormalities showed only partial recovery following cuprizone withdrawal. In contrast, cuprizone elicited little or no detectable change in these forebrain white-matter regions and in other brain areas in aged mice. However, the cerebellar nuclei remained susceptible at both ages, exhibiting persistent MTR decreases and T2-weighted signal increases, corroborated by histological evidence of demyelination and gliosis. T1-weighted signal increased broadly in adult, but not in aged, mice during intoxication, consistent with cuprizone-associated oxidative stress. Together, these findings demonstrate pronounced age- and region-dependent effects of cuprizone and identify the cerebellar nuclei as a sensitive target of demyelination across the lifespan. Moreover, the non-invasive nature of MRI enables efficient assessment of regional differences over time.
Related
- Betaine Attenuates Cuprizone-Induced Cortical Demyelination: The Role of the WNT4/mTOR Signalling Pathway in Regulating Astrogliosis and Synaptic Integrity.
- Sustaining Integrated Care for Vulnerable Youth: A Longitudinal Case Study of the Regina Intersectoral Partnership (TRiP)
- New tests for trials of very few patients using longitudinal data - a case-study in Autosomal Recessive Cerebellar Ataxias
- Dynamic association of APLNR with astrocytic remodeling in the cuprizone-treated corpus callosum
- Validity Gates Expose Limits of Longitudinal Multimodal Parkinson Disease Prediction
BibTeX
@article{shimshek2026cerebellar,
title = {{Cerebellar nuclei remain vulnerable to cuprizone-induced demyelination in adult and aged mice: A longitudinal multimodal MRI-histology study}},
author = {Derya R. Shimshek and Stefan Zurbruegg and Anna Neuhaus and Arno Doelemeyer and Nicolau Beckmann},
journal = {Aging Brain},
year = {2026},
month = oct,
doi = {10.1016/j.nbas.2026.100171},
url = {https://doi.org/10.1016/j.nbas.2026.100171},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Cerebellar nuclei remain vulnerable to cuprizone-induced demyelination in adult and aged mice: A longitudinal multimodal MRI-histology study
AU - Derya R. Shimshek
AU - Stefan Zurbruegg
AU - Anna Neuhaus
AU - Arno Doelemeyer
AU - Nicolau Beckmann
PY - 2026
DA - 2026/10/17
JO - Aging Brain
DO - 10.1016/j.nbas.2026.100171
UR - https://doi.org/10.1016/j.nbas.2026.100171
AB - Age is a major determinant of demyelination and remyelination capacity. Here, we investigated age-dependent brain responses to acute cuprizone exposure in female C57BL/6 mice using longitudinal multimodal Magnetic resonance imaging (MRI) and histological analyses. Our aim was to determine whether any brain region in very old animals remains susceptible to cuprizone-induced pathology. Adult (6-month-old) and aged (18-month-old) mice received 0.2% cuprizone in the diet for 5 weeks, followed by 4 weeks of recovery on normal chow, with in vivo MRI performed at baseline, during intoxication, and throughout recovery. Magnetization transfer ratio (MTR) and T2-weighted signal were used as MRI surrogates of myelin integrity and neuroinflammation, respectively, whereas T1-weighted signal was assessed as a potential marker sensitive to oxidative stress. In adult mice, cuprizone induced robust and region-specific pathology, including reduced MTR and increased T2-weighted signal in the corpus callosum, accompanied by microgliosis, astrocytosis, and increased APP-positive dystrophic neurites. These abnormalities showed only partial recovery following cuprizone withdrawal. In contrast, cuprizone elicited little or no detectable change in these forebrain white-matter regions and in other brain areas in aged mice. However, the cerebellar nuclei remained susceptible at both ages, exhibiting persistent MTR decreases and T2-weighted signal increases, corroborated by histological evidence of demyelination and gliosis. T1-weighted signal increased broadly in adult, but not in aged, mice during intoxication, consistent with cuprizone-associated oxidative stress. Together, these findings demonstrate pronounced age- and region-dependent effects of cuprizone and identify the cerebellar nuclei as a sensitive target of demyelination across the lifespan. Moreover, the non-invasive nature of MRI enables efficient assessment of regional differences over time.
SN - 2589-9589
ER -