Affiliations: [a] Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| [b] YCU Center for Novel and Exploratory Clinical Trials (Y-NEXT), Yokohama City University Hospital, Yokohama, Japan
| [c] Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Correspondence:
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Correspondence to: Ken Arai, PhD, Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Room 2401 Charlestown, MA 02129-2000, USA. Tel.: +1 617 724 9530, Fax: +1 617 726 7830; E-mail: [email protected].
Note: [1] These authors equally contributed to this work.
Abstract: Background:Alzheimer’s disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. Objective:This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. Methods:We conducted behavioral tests for spatial learning and memory in 5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. Results:Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1, Per2, and Cry1 is also observed. Conclusions:This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies.
