Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson’s disease

Su, Xiaoli; Dai, Shaobing; Fang, Yi; Tang, Jiahui; Wang, Zhiyun; Li, Yaolin; Song, Zhe; Chen, Ying; Liu, Yi; Zhao, Guohua; Zhang, Baorong; Pu, Jiali

doi:10.1016/j.jare.2023.03.004

Cited by 21 publications

(11 citation statements)

References 37 publications

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“…The authors demonstrated that MMP-9 and cleaved β-DG were upregulated in both MPTP-induced PD and A53T mice, while the polarized localization of β-DG and AQP4 to astrocyte endfeet was reduced. MMP-9 inhibition restored basement membrane-astrocyte endfeet-AQP4 integrity and attenuated the loss of DA-ergic neurons [130]. The results of this study demonstrated the impact of AQP4 depolarization in glymphatic dysfunction and the aggravation of PD-like pathologies and revealed the important role of MMP-9-mediated β-DG cleavage in regulating AQP4 polarization and maintaining glymphatic function.…”

Section: Aqp4 Dysregulation In Pdsupporting

confidence: 52%

“…The restoration of AQP4 polarization led to the downregulation of neurodegeneration-associated metabolites, uremic toxins as well as secondary metabolites. At the same time, the authors revealed the upregulation of polyunsaturated fatty acids, nucleotides, phosphoglycerides, and other biosynthetic intermediates [130]. The restoration of AQP4 polarization led to the recovery of markers of anti-oxidative stress, mitophagy, and apoptosis, as well as modulators of neurotransmission and extracellular signaling.…”

Section: Aqp4 and Cns Homeostasismentioning

confidence: 91%

“…Simultaneously, it was shown that α-synucleinactivated microglia produce extracellular glutamate, aggravating excitotoxicity in PD [155]. It was shown that the MPTP-induced PD model in mice was characterized by disrupted AQP4 polarization and marked changes in metabolic profile mainly composed of lipids and lipid-like molecules as well as organic acids and derivatives [130]. The restoration of AQP4 polarization led to the downregulation of neurodegeneration-associated metabolites, uremic toxins as well as secondary metabolites.…”

Section: Aqp4 and Cns Homeostasismentioning

confidence: 99%

“…Recent studies exploring the role of matrix metalloproteinase-9 (MMP-9)-mediated β-dystroglycan (β-DG) cleavage in the regulation of AQP4 polarity-mediated glymphatic system in PD have revealed reduced perivascular influx and efflux of CSF tracers in an MPTP-induced PD model in mice associated with impaired AQP4 polarization [130]. The application of TGN-020, an AQP4 inhibitor, evoked the aggravation of reactive astrogliosis, glymphatic drainage restriction, and the loss of nigral DA-ergic neurons in an MPTP-induced PD model.…”

Section: Aqp4 Dysregulation In Pdmentioning

confidence: 99%

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Aquaporin-4 and Parkinson’s Disease

Lapshina,

Ekimova

2024

IJMS

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The water-selective channel aquaporin-4 (AQP4) is implicated in water homeostasis and the functioning of the glymphatic system, which eliminates various metabolites from the brain tissue, including amyloidogenic proteins. Misfolding of the α-synuclein protein and its post-translational modifications play a crucial role in the development of Parkinson’s disease (PD) and other synucleopathies, leading to the formation of cytotoxic oligomers and aggregates that cause neurodegeneration. Human and animal studies have shown an interconnection between AQP4 dysfunction and α-synuclein accumulation; however, the specific role of AQP4 in these mechanisms remains unclear. This review summarizes the current knowledge on the role of AQP4 dysfunction in the progression of α-synuclein pathology, considering the possible effects of AQP4 dysregulation on brain molecular mechanisms that can impact α-synuclein modification, accumulation and aggregation. It also highlights future directions that can help study the role of AQP4 in the functioning of the protective mechanisms of the brain during the development of PD and other neurodegenerative diseases.

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Section: Aqp4 Dysregulation In Pdsupporting

confidence: 52%

Section: Aqp4 and Cns Homeostasismentioning

confidence: 91%

Section: Aqp4 and Cns Homeostasismentioning

confidence: 99%

Section: Aqp4 Dysregulation In Pdmentioning

confidence: 99%

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Aquaporin-4 and Parkinson’s Disease

Lapshina,

Ekimova

2024

IJMS

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“…A study on an animal model of AD showed that animals develop astrogliosis and the localization pattern of AQP4 changes [54]. In a mouse PD model, astrogliosis and AQP4 depolarization contributed to glymphatic dysfunction [55]. Disturbances in the expression and localization of AQP4 may be associated with impaired glymphatic flow and may contribute to the pathological processes of neurodegeneration [56].…”

Section: Astrocytes and The Role Of Aqp4mentioning

confidence: 99%

Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration

Szlufik,

Kopeć,

Szleszkowski

et al. 2024

Cells

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The key to the effective treatment of neurodegenerative disorders is a thorough understanding of their pathomechanism. Neurodegeneration and neuroinflammation are mutually propelling brain processes. An impairment of glymphatic system function in neurodegeneration contributes to the progression of pathological processes. The question arises as to how neuroinflammation and the glymphatic system are related. This review highlights the direct and indirect influence of these two seemingly independent processes. Protein aggregates, a characteristic feature of neurodegeneration, are correlated with glymphatic clearance and neuroinflammation. Glial cells cannot be overlooked when considering the neuroinflammatory processes. Astrocytes are essential for the effective functioning of the glymphatic system and play a crucial role in the inflammatory responses in the central nervous system. It is imperative to acknowledge the significance of AQP4, a protein that exhibits a high degree of polarization in astrocytes and is crucial for the functioning of the glymphatic system. AQP4 influences inflammatory processes that have not yet been clearly delineated. Another interesting issue is the gut–brain axis and microbiome, which potentially impact the discussed processes. A discussion of the correlation between the functioning of the glymphatic system and neuroinflammation may contribute to exploring the pathomechanism of neurodegeneration.

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The Implication and Application of Brain Glymphatic System in Multiple Diseases

Du,

Yan,

Wang

et al. 2024

Advanced Therapeutics

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The glymphatic system within the central nervous system (CNS) facilitates the exchange and elimination of cerebrospinal fluid (CSF) and interstitial fluid (ISF), aiding in the removal of potentially poisonous metabolic wastes to maintain brain stability. Sleep and Aquaporin‐4 (AQP‐4) expression positively regulate the glymphatic system. When sleep is disturbed and AQP‐4 polarization is inhibited, the glymphatic system is impaired, leading to the inability to effectively eliminate soluble wastes from the brain. This disruption can potentially contribute to, or accelerate, the progression of various CNS diseases, such as Alzheimer's disease and Parkinson's disease, as well as non‐CNS diseases, like diabetes mellitus and hypertension. Therefore, the normal functioning of the glymphatic system is essential for the recovery from both CNS diseases and non‐CNS diseases. In this review, an overview of the constituents and functions of the glymphatic system in the brain, specifically highlighting the glymphatic system lesions in different diseases is provided. Additionally, currently unresolved questions pertaining to this topic are summarized. Ultimately, the cerebral glymphatic system is expected to be a novel and promising target for the diagnosis and treatment of multiple diseases.

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Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson’s disease

Cited by 21 publications

References 37 publications

Aquaporin-4 and Parkinson’s Disease

Aquaporin-4 and Parkinson’s Disease

Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration

The Implication and Application of Brain Glymphatic System in Multiple Diseases

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