Abstract
Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.
Highlights
Clemastine fumarate is a first-generation H1-antihistamine that is mainly used for relieving symptoms of allergic reactions primarily by competing with histamine to bind H1 receptors (Blazsó and Gábor, 1997)
This result indicates that the short-term memory deficits of the aged APP/PS1 mice can be rescued by clemastine treatment
By immunolabeling myelin basic protein (MBP), the main protein component of myelin (Liu et al, 2021), we found that compared with the WT mice, the MBP immunofluorescence intensity was decreased for the APP/PS1 mice (Figures 5A–C), which was reverted by the treatment of clemastine (Figures 5A–C)
Summary
Clemastine fumarate is a first-generation H1-antihistamine that is mainly used for relieving symptoms of allergic reactions primarily by competing with histamine to bind H1 receptors (Blazsó and Gábor, 1997). In addition to its anti-inflammatory effects, clemastine shows antimuscarinic type-1 receptors effects In recent years, it was found clemastine, among other antimuscarinic compounds, can significantly induce oligodendrocyte precursor cell (OPC) differentiation and myelination (Mei et al, 2014), accelerating the remyelination process in animal models featured. A phase 2 clinical trial on using clemastine for treating multiple sclerosis (MS) showed that remyelination could be achieved during the chronic neurodegeneration process (Green et al, 2017). These studies collectively strongly suggest clemastine is a potent stimulator of myelin formation with a good safety profile. The precise mechanisms of clemastine promoting remyelination are still unknown
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