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

Xie, Yuan-Yuan; Pan, Tingting; Xu, De-en; Huang, Xin; Tang, Yong; Huang, Wenhui; Chen, Rui; Lu, Li; Chi, Hao; Ma, Quan-Hong

doi:10.3389/fcell.2021.733945

Cited by 14 publications

(19 citation statements)

References 48 publications

(71 reference statements)

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“…Increased deposition of amyloid plaques extracellularly and accumulation of hyperphosphorylated tau proteins intracellularly are two pathological hallmarks of Alzheimer's disease [44,45]. Although the mechanisms underlying increased deposition of Aβ and phosphorylated tau proteins in the brain of LOAD patients are unknown, several mouse models that overexpress mutant human amyloid precursor protein (APP) or APP plus mutant human presenilin 1 or mutant form of human microtubule-associated protein tau P301S have been generated and used to study the mechanisms, whereby Aβ and hyperphosphorylated tau proteins promote AD pathophysiology [24,25,40,41,49,[70][71][72][73][74][75][76]. Emerging evidence from these animal studies indicates that increased Aβ and tau phosphorylation promote brain cell senescence and that cellular senescence plays a critical role in the neuropathology and memory decline in AD.…”

Section: Evidence Of Cellular Senescence In Ad Model Micementioning

confidence: 99%

“…These mice display a significant increase in brain Aβ load and memory impairment and have been widely used as a murine model of familial AD. Emerging evidence shows that various types of brain cells, including oligodendrocyte precursor cells (OPCs), astrocytes, microglia, and neurons, express higher levels of senescence markers p16, p21, and SA-β-gal in these familial AD model mice [25,40,70,71] Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and is involved in many biological processes. Hou et al reported that, associated with a decline in NAD+ level in the brain, various types of brain cells in APP/PS1 mice displayed a senescence phenotype, including increased SA-β-gal activity, as well as increased p16 and p21 expression, [71].…”

Section: Mice Overexpressing Amyloid Precursor Protein (App)mentioning

confidence: 99%

“…Accumulation of β-amyloid (Aβ) peptides in the brain is a pathological feature of AD [44,45]. Although the mechanism by which Aβ promotes neuronal degeneration and memory loss in AD is still controversial, accumulated evidence indicates that Aβ is a potent inducer of cell senescence [25,40,50,70,71,[80][81][82][83][84][85][86]. Wei et al showed that the expression of cell senescence marker p16 is significantly increased in neurons, although not in astrocytes or microglia, in 5XFAD transgenic mice, which overexpress human amyloid β (A4) precursor protein 695 (APP) with three mutations detected in familial Alzheimer's disease (FAD) and human presenilin 1 (PS1) harboring two FAD mutations [40].…”

Section: Aβ Oligomersmentioning

confidence: 99%

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Aging, Cellular Senescence, and Alzheimer’s Disease

Liu

2022

IJMS

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Aging is the greatest risk factor for late-onset Alzheimer’s disease (LOAD), which accounts for >95% of Alzheimer’s disease (AD) cases. The mechanism underlying the aging-related susceptibility to LOAD is unknown. Cellular senescence, a state of permanent cell growth arrest, is believed to contribute importantly to aging and aging-related diseases, including AD. Senescent astrocytes, microglia, endothelial cells, and neurons have been detected in the brain of AD patients and AD animal models. Removing senescent cells genetically or pharmacologically ameliorates β-amyloid (Aβ) peptide and tau-protein-induced neuropathologies, and improves memory in AD model mice, suggesting a pivotal role of cellular senescence in AD pathophysiology. Nonetheless, although accumulated evidence supports the role of cellular senescence in aging and AD, the mechanisms that promote cell senescence and how senescent cells contribute to AD neuropathophysiology remain largely unknown. This review summarizes recent advances in this field. We believe that the removal of senescent cells represents a promising approach toward the effective treatment of aging-related diseases, such as AD.

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Section: Evidence Of Cellular Senescence In Ad Model Micementioning

confidence: 99%

Section: Mice Overexpressing Amyloid Precursor Protein (App)mentioning

confidence: 99%

Section: Aβ Oligomersmentioning

confidence: 99%

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Aging, Cellular Senescence, and Alzheimer’s Disease

Liu

2022

IJMS

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“…This suggests that regulating OPC survival is not only protective for recovery from myelin injury, but is beneficial for rescuing synaptic function in hypoxia. Clemastine has also showed effects on remyelination in other disease models such as compression neuropathy ( Lee et al, 2021 ), Alzheimer’s disease ( Xie et al, 2021 ) and MS ( Green et al, 2017 ). The mechanisms of action are still unclear, but tests showed prevention of OPC loss, an increase in myelination expression, prevention of senescence ( Xie et al, 2021 ), an increase in myelin thickness, and a decrease in the latency of impulse conduction ( Lee et al, 2021 ).…”

Section: Disease and Treatmentmentioning

confidence: 99%

“…Clemastine has also showed effects on remyelination in other disease models such as compression neuropathy ( Lee et al, 2021 ), Alzheimer’s disease ( Xie et al, 2021 ) and MS ( Green et al, 2017 ). The mechanisms of action are still unclear, but tests showed prevention of OPC loss, an increase in myelination expression, prevention of senescence ( Xie et al, 2021 ), an increase in myelin thickness, and a decrease in the latency of impulse conduction ( Lee et al, 2021 ). Clemastine fumarate is a first generation H1 anti-histamine used to relieve allergic reactions by competing with H1 receptors, other than M1R.…”

Section: Disease and Treatmentmentioning

confidence: 99%

Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics

et al. 2022

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The development of neuronal circuitry required for cognition, complex motor behaviors, and sensory integration requires myelination. The role of glial cells such as astrocytes and microglia in shaping synapses and circuits have been covered in other reviews in this journal and elsewhere. This review summarizes the role of another glial cell type, oligodendrocytes, in shaping synapse formation, neuronal circuit development, and myelination in both normal development and in demyelinating disease. Oligodendrocytes ensheath and insulate neuronal axons with myelin, and this facilitates fast conduction of electrical nerve impulses via saltatory conduction. Oligodendrocytes also proliferate during postnatal development, and defects in their maturation have been linked to abnormal myelination. Myelination also regulates the timing of activity in neural circuits and is important for maintaining the health of axons and providing nutritional support. Recent studies have shown that dysfunction in oligodendrocyte development and in myelination can contribute to defects in neuronal synapse formation and circuit development. We discuss glutamatergic and GABAergic receptors and voltage gated ion channel expression and function in oligodendrocyte development and myelination. We explain the role of excitatory and inhibitory neurotransmission on oligodendrocyte proliferation, migration, differentiation, and myelination. We then focus on how our understanding of the synaptic connectivity between neurons and OPCs can inform future therapeutics in demyelinating disease, and discuss gaps in the literature that would inform new therapies for remyelination.

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

Cited by 14 publications

References 48 publications

Aging, Cellular Senescence, and Alzheimer’s Disease

Aging, Cellular Senescence, and Alzheimer’s Disease

Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics

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