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

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.

Positive association between plasmatic levels of orexin A and the endocannabinoid-derived 2-arachidonoyl lysophosphatidic acid in Alzheimer’s disease

“…In line with these data, deregulation of the orexinergic system has been documented in AD patients, who show increases in orexin-A (OX-A) levels in the CSF ( Osorio et al, 2016 ; Gabelle et al, 2017 ; Shimizu et al, 2020 ), and in AD animal models ( Liu et al, 2018 ; Zhao et al, 2022 ). OX-A (or hypocretin 1) is a 33-amino acid peptide produced by a small number of neurons strictly localized in the lateral hypothalamic area ( Peyron et al, 1998 ), which send projections widely distributed throughout the brain ( Peyron et al, 1998 ; Date et al, 1999 ; Nambu et al, 1999 ).…”

Research Progress on the Pathogenesis of Circadian Rhythm Sleep-Wake Disorders

“…Orexin-Related Drugs for Sleep-Wake Disorders is in a preclinical research program. The orexinergic system is closely related to neurodegeneration in AD patients, but the current study cannot determine whether it is positively or negatively related [9].…”

“…Small cell neurons in the paraventricular nucleus of the hypothalamus are stimulated to synthesize and release corticotropin-releasing hormone (CRH) and AVP, through the pituitary portal system in the median hypothalamic eminence, in the anterior pituitary, stimulate corticosteroid cells to release adrenocorticotropic Hormone (ACTH) [11], ACTH reaches the adrenal cortex through the blood to promote the secretion of adrenal glucocorticoids, and negative feedback acts on the paraventricular nucleus and the adenohypophysis to inhibit CRH and ACTH. Glucocorticoids and their receptors (GR) are distributed in major systems in the body and are important substances to maintain the body's homeostasis [6,9] (fig2).…”

Effect of a dual orexin receptor antagonist on Alzheimer's disease: Sleep disorders and cognition

“…However, the changes in sleep patterns from preclinical to clinical AD and the causal relationship with AD remain unclear. Few contradictory findings exist on the level of orexin in the CSF or plasma of AD patients ( 59 ). The neurobiological basis for explaining the relationship between sleep/wakefulness disorder and cognitive decline in AD remains to be elucidated.…”