Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 14; pp. 2292 - 2307.e5
• Main Authors: Chen, Jing-Fei, Liu, Kun, Hu, Bo, Li, Rong-Rong, Xin, Wendy, Chen, Hao, Wang, Fei, Chen, Lin, Li, Rui-Xue, Ren, Shu-Yu, Xiao, Lan, Chan, Jonah R., Mei, Feng
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Inc 21.07.2021; Elsevier Limited
• Subjects: Acetylcholine receptors (muscarinic); Age; Aging; Alzheimer's disease; Animal models; APP/PS1; Autopsy; clemastine; Cognitive ability; Demyelination; Gene expression; Hippocampus; Histology; Memory; Myelination; Neurodegenerative diseases; oligodendroglia; Presenilin 1; Proteins; SPW-R; Substantia alba; Substantia grisea; myelination; SPW-R; clemastine; demyelination; APP/PS1; oligodendroglia
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2021.05.012

Severe cognitive decline is a hallmark of Alzheimer’s disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment. [Display omitted] •New myelin formation is increased in adult APP/PS1 mice•Extensive myelin loss occurs in APP/PS1 mice and individuals with AD•Pro-myelinating strategies enhance myelin renewal and alleviate myelin loss in APP/PS1 mice•Enhanced myelin renewal rescues deficits in cognition and hippocampal physiology in APP/PS1 mice Chen et al. demonstrate that myelin formation is increased in APP/PS1 mice, reminiscent of a regenerative response to extensive demyelination, and that pro-myelinating strategies enhance myelin renewal, rescue cognitive deficits, and increase hippocampal sharp wave ripples in APP/PS1 mice.