Abstract
The pathological hallmarks of Parkinson’s disease (PD), a neurodegenerative disorder, are the selective loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and the presence of α-synuclein (α-syn) aggregates in the form of Lewy bodies/Lewy neurites (LBs/LNs) in neurons. Recent studies have indicated that aquaporin 4 (AQP4), as a predominant water channel protein in the brain, is involved in the progression of Parkinson’s disease (PD). However, it remains unclear whether AQP4 expression affects α-syn pathology in Parkinson’s disease. In this study, we established a progressive PD model by subjecting AQP4 null (AQP4+/−) mice to bilateral intrastriatal injection of α-syn preformed fibrils (PFFs) and investigated the effect of decreased AQP4 expression on the development of PD. We found that decreased expression of AQP4 accelerated pathologic deposition of α-syn and facilitated the loss of dopamine neurons and behavioral disorders. Draining of macromolecules from the brain via the glymphatic pathway was slowed due to decreased AQP4 expression. Taken together, these findings indicate that decreased AQP4 expression may aggravate PD-like pathology, possibly via impairment of the glymphatic pathway.
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All relevant data supporting the findings of this study are either included within the article and its Supplementary Information files or are available upon request from the corresponding author.
Abbreviations
- AQP4:
-
Water channel aquaporin 4
- WT:
-
Wild type
- SN:
-
Substantia nigra
- α-syn PFFs:
-
α-Syn-preformed fibrils
- PBS:
-
Phosphate-buffered saline
- TH:
-
Tyrosine hydroxylase
- PD:
-
Parkinson’s disease
- CNS:
-
Central nervous system
- CSF:
-
Cerebrospinal fluid
- TBI:
-
Traumatic brain injury
- ISF:
-
Interstitial fluid
- Mpi:
-
Months post-injection
- AQP4+/--PFFs:
-
α-Syn PFFs-injected AQP4+/- mice
- WT-PFFs:
-
WT mice treated with α-syn PFFs
- LBs/LNs:
-
Lewy-bodies/Lewy-neurites
- SNpc:
-
Substantia nigra pars compacta
- ALS:
-
Amyotrophic lateral sclerosis
- M1,M2:
-
Motor cortex
- Pir:
-
Piriform cortex
- S1,S2:
-
Somatosensory cortex
- Cg1,Cg2:
-
Cingulate cortex
- DI,CI:
-
Insular cortex
- MPP + :
-
1-Methyl-4-phenylpyridinium
- MPTP:
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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The research was supported by the National Natural Science Foundation of China (No. 81671267).
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Huili Cui, Hanliu and Danhao Xia.ChiQin. The first draft of the manuscript was written by Huili Cui, Haiyan Tian, Xinhui Zheng, and Wenkang Wang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Cui, H., Wang, W., Zheng, X. et al. Decreased AQP4 Expression Aggravates ɑ-Synuclein Pathology in Parkinson’s Disease Mice, Possibly via Impaired Glymphatic Clearance. J Mol Neurosci 71, 2500–2513 (2021). https://doi.org/10.1007/s12031-021-01836-4
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DOI: https://doi.org/10.1007/s12031-021-01836-4