Orexin A peptidergic system: comparative sleep behavior, morphology and population in brains between wild type and Alzheimer\u2019s disease mice

Peng Zhao,Yaqian You,Gaoshang Chai,Gen Yan,Qing Wang,Yanjun Zhou,Zhewu Jin,Hongxu Sun,Zhe Wang

doi:10.1007/s00429-021-02447-w

Peng Zhao, Yaqian You + Show 7 more

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https://doi.org/10.1007/s00429-021-02447-w

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Abstract

Sleep disturbance is common in patients with Alzheimer’s disease (AD), and orexin A is a pivotal neurotransmitter for bidirectionally regulating the amyloid-β (Aβ) deposition of AD brain and poor sleep. In the present study, we examined the characteristic of sleep–wake architecture in APPswe/PSldE9 (APP/PS1) and Aβ-treated mice using electroencephalogram (EEG) and electromyographic (EMG) analysis. We compared the expression of orexin A, distribution, and morphology of the corresponding orexin A-positive neurons using innovative methods including three-dimensional reconstruction and brain tissue clearing between wild type (WT) and APP/PS1 mice. Results from our study demonstrated that increased wakefulness and reduced NREM sleep were seen in APP/PS1 and Aβ treated mice, while the expression of orexin A was significantly upregulated. Higher density and distribution of orexin A-positive neurons were seen in APP/PS1 mice, with a location of 1.06 mm–2.30 mm away from the anterior fontanelle compared to 1.34 mm–2.18 mm away from the anterior fontanelle in WT mice. These results suggested that the population and distribution of orexin A may play an important role in the progression of AD.

Highlights

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by diffused extracellular amyloid plaques deposition and intracellular neurofibrillary tangles (NFT) that results in progressive dementia associated with cognitive impairment, memory loss, and
Animal and human studies have demonstrated that the accumulation of the amyloid-β (Aβ) peptide, a primary cause of amyloid plaques, is a critical event in the pathogenesis of AD as well as poor sleep (Vanderheyden et al 2018; Brown et al 2016)
Sleep abnormalities have been observed for decades in AD (Weng et al 2020)

Summary

Introduction

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by diffused extracellular amyloid plaques deposition and intracellular neurofibrillary tangles (NFT) that results in progressive dementia associated with cognitive impairment, memory loss, andPeng Zhao, Yaqian You, and Zhe Wang have contributed to this paper.Sleep disturbances are commonly seen in patients with AD and affect approximately 25%–60% of patients (Lim et al 2014). Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by diffused extracellular amyloid plaques deposition and intracellular neurofibrillary tangles (NFT) that results in progressive dementia associated with cognitive impairment, memory loss, and. Animal and human studies have demonstrated that the accumulation of the amyloid-β (Aβ) peptide, a primary cause of amyloid plaques, is a critical event in the pathogenesis of AD as well as poor sleep (Vanderheyden et al 2018; Brown et al 2016). Intracerebroventricular administration of Aβ has been identified to serve as a useful AD model which can trigger cognitive impairment, memory defects, and other AD-like alterations in the brain (Zhang et al 2019b; Facchinetti et al 2018). Many transgenic flies of AD models overexpressing Aβ peptides have shown

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