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

Chen, Jing-Fei; Liu, Kun; Hu, Bo; Li, Rongrong; Xin, Wendy; Chen, Hao; Wang, Fei; Chen, Lin; Li, Ruixue; Ren, Shen; Xiao, Lan; Chan, Jonah R.; Mei, Feng

doi:10.1016/j.neuron.2021.05.012

Cited by 212 publications

(186 citation statements)

References 72 publications

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“…In our previous study, we found that chronic treatment of clemastine reduces brain Aβ deposition and rescues the cognitive deficits of 7-month-old APPSwe/PS1dE9 (APP/PS1) mice ( Li et al, 2021 ). Consistent with that, another recent study also shows that chronic treatment of clemastine can improve the memory of young APP/PS1 mice and induces significant myelin formation concomitantly ( Chen et al, 2021 ). In this study, we investigated if chronic treatment of clemastine has therapeutic effects for aged APP/PS1 mice.…”

Section: Introductionsupporting

confidence: 69%

“…Comparing to MS, the degeneration process of AD is rather gradual as prominent brain pathology, and the cognitive deficits commonly appear at the later stages of the disease. In this study, by using aged APP/PS1 mice instead of young mice that were used in the previous studies ( Chen et al, 2021 ; Li et al, 2021 ), we believe it recaptures the features of AD at a later stage and enables more objective evaluation for the treatment ( Huang et al, 2016 ; Denver et al, 2018 ). Our finding that chronic treatment of clemastine can enhance myelin formation and prevents myelin degeneration in the aged AD mice indicates that clemastine potentially could induce remyelination process even for the patients with abundant Aβ deposition at the advanced stages.…”

Section: Discussionmentioning

confidence: 99%

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Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

Xie

Pan²,

Xu³

et al. 2021

Front. Cell Dev. Biol.

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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.

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Section: Introductionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

Xie

Pan²,

Xu³

et al. 2021

Front. Cell Dev. Biol.

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“…The behavioral function of aged mice was improved when it comes to remyelination, which showed through the up-regulated MBP ( Bao et al, 2021 ). Recent studies have shown that enhanced remyelination reverses cognitive dysfunction in a murine model of Alzheimer’s disease ( Chen et al, 2021a ). This finding was also confirmed in the chronic cerebral hypoperfusion rat model ( Li et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is worth noting that no studies have been conducted on the relationship between PND and demyelination. On the contrary, remyelination contributes to the improvement of cognitive function ( Del Giovane and Ragnini-Wilson, 2018 ; Chen et al, 2021a ), which might be helpful in the treatment of PND. Besides, neuronal function can also benefit from remyelination and mainly manifested by synaptic function ( Del Giovane and Ragnini-Wilson, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

Zhang

Zhou

et al. 2021

Front. Pharmacol.

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Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/β-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.

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“…Extensive myelin loss was observed in APP mice and in individuals with AD both by in vivo imaging as well as in histopathological studies [170][171][172]. Recent studies showed that myelin loss drives Aβ deposition, and that enhancing myelin renewal in turn alleviate the cognitive deficits in APP/PS1 mice [173] and in 5×FAD mice [174]. A number of studies have applied in vivo and ex vivo DTI for detecting the white matter impairment, which appears preceding the anatomical changes on structural MRI including the APPswe, APP/PS1, TgCRND8, APP NL-G-F , 3×Tg, CVN-AD and 5×FAD mice [81,93,97,175-183] (Table 3).…”

Section: Dtimentioning

confidence: 99%

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

Ni¹

2021

Preprint

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Amyloid-beta plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant amyloid-beta and tau accumulation induce neuroinflammation, cerebrovascular alterations, synaptic deficits, functional deficits, and neurodegeneration, leading to cognitive impairment. Animal models recapitulating the amyloid-beta pathology such as transgenic, knock-in mouse and rat models have facilitated the understanding of disease mechanisms and development of therapeutics targeting at amyloid-beta. There is a rapid advance in high-field MR in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences such as diffusion tensor imaging, arterial spin labelling, resting-state functional MRI, anatomical MRI, MR spectroscopy as well as contrast agents have been developed for the applications in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole brain field-of-view. MRI have been utilized to visualize non-invasively the amyloid-beta deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, cerebrovascular and glymphatic system in animal models of amyloidosis. Many of the readouts are translational in clinical MRI in the brain of patients with Alzheimer’s disease. In this review, we summarize the recent advance of using MRI for visualizing the pathophysiology in amyloidosis animal model. We discuss the outstanding challenges in brain imaging using MRI in small animal and propose future outlook in visualizing amyloid-beta-related alterations in brain of animal models.

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

Cited by 212 publications

References 72 publications

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

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