Moxibustion improves hypothalamus Aqp4 polarization in APP/PS1 mice: Evidence from spatial transcriptomics

Abstract

Aquaporin-4 (AQP4) is highly polarized to perivascular astrocytic endfeet. Loss of AQP4 polarization is associated with many diseases. In Alzheimer’s disease (AD), AQP4 loses its normal location and thus reduces the clearance of amyloid-β plaques and tau protein. Clinical and experimental studies showed that moxibustion can improve the learning and memory abilities of AD. To explore whether moxibustion can affect the polarization of AQP4 around the blood-brain barrier (BBB), we used spatial transcriptomics (ST) to analyze the expression and polarization of Aqp4 in wild-type mice, APP/PS1 mice, and APP/PS1 mice intervened by moxibustion. The results showed that moxibustion improved the loss of abnormal polarization of AQP4 in APP/PS1 mice, especially in the hypothalamic BBB. Besides, the other 31 genes with Aqp4 as the core have similar depolarization in APP/PS1 mice, most of which are also membrane proteins. The majority of them have been reversed by moxibustion. At the same time, we employed the cerebrospinal fluid circulation gene set, which was found to be at a higher level in the group of APP/PS1 mice with moxibustion treatment. Finally, to further explore its mechanism, we analyzed the mitochondrial respiratory chain complex enzymes closely related to energy metabolism and found that moxibustion can significantly increase the expression of mitochondrial respiratory chain enzymes such as Cox6a2 in the hypothalamus, which could provide energy for mRNA transport. Our research shows that increasing the polarization of hypothalamic Aqp4 through mitochondrial energy supply may be an important target for moxibustion to improve cognitive impairment in APP/PS1 mice.

A bibliometric analysis of the glymphatic system in cognition from 2009 to 2023

“…Electroacupuncture treatment reduced Aβ level, enhanced perivascular in ux in the GS, inhibited astrocyte reactivity, and improved AQP4 polarity in the SAMP8 mouse model of AD [54]. In addition, moxibustion increased the polarization of hypothalamic AQP4 and ameliorated cognitive impairment in APP/PS1 mice [55]. Therefore, the current authors speculate that acupuncture can promote cognitive function through glymphatic-uid transport by reducing Aβ accumulation and through an interesting therapeutic target of AQP4.…”

Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood–Brain Barrier

“…In addition, it has been reported that the localization of AQP4 also depends on the correct organization of the astrocytic endfeet, which, in turn, depends on the assembly of the gap junctions (GJs), formed by connexins 43 and 30 (Cx43 and Cx30, respectively), between the endfeet; microhemorrhages are indeed more frequent in C43-deficient mice [7]. Actually, brain edema has been evidenced in many pathological conditions, from cancer to stroke, and, in many cases, altered production and/or localization of AQP4 has been found, while, at the same time, the involvement of AQP4 in all these alterations suggests this protein and its organization as a therapeutic target [75][76][77][78][79]. Recently, an AQP4 variant with a C-terminal extension (AQP4x) has been also isolated, and it has been shown that it plays a role in BBB integrity [80].…”

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…Current research has established that diminished AQP4 expression leads to reduced Aβ clearance and causes Aβ accumulation, leading to deficiencies in memory and learning ability and the development of CI ( Hubbard et al, 2018 ; Chandra et al, 2021 ; Fang et al, 2021 ; Liu et al, 2022 ; Wang et al, 2022 ; Vasciaveo et al, 2023 ). In addition to regulating water homeostasis, AQP4 also activates astrocytes ( Yang et al, 2022 ; Liu et al, 2023 ), and outside of the brain, it is expressed by IHCs ( Christensen et al, 2009 ; Nishio et al, 2013 ). AQP4 is now widely believed to be involved in maintaining the osmotic balance during the K + cycle as well as the ionic balance of the endolymphatic fluid ( Li and Verkman, 2001 ; Mhatre et al, 2002 ).…”