Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits

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Abstract

Background

Preventing or reducing amyloid-beta (Aβ) accumulation in the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Recent studies showed that the water channel aquaporin-4 (AQP4) mediates soluble Aβ clearance from the brain parenchyma along the paravascular pathway. However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent.

Results

Here, we reported that the deletion of AQP4 exacerbated cognitive deficits of 12-moth old APP/PS1 mice, with increases in Aβ accumulation, cerebral amyloid angiopathy and loss of synaptic protein and brain-derived neurotrophic factor in the hippocampus and cortex. Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignficant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples.

Conclusions

These results suggest that AQP4 attenuates Aβ pathogenesis despite its potentially inflammatory side-effects, thus serving as a promising target for treating AD.

Electronic supplementary material

The online version of this article (doi:10.1186/s13024-015-0056-1) contains supplementary material, which is available to authorized users.

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Most cited references 48

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Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

Jeffrey J. Iliff, Hedok Lee, Mei Yu … (2013)

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.

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Interleukin-6, a Major Cytokine in the Central Nervous System

María Erta, Albert Quintana, Juan Hidalgo (2012)

Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.

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Co-expression of multiple transgenes in mouse CNS: a comparison of strategies.

Joanna Jankowsky, Hilda H Slunt, Tamara Ratovitski … (2001)

The introduction of two transgenes into one animal is increasingly common as transgenic experiments become more sophisticated. In this study we examine two strategies for creating double transgenic founders from a single microinjection. In the first approach, two constructs, each with its own promoter element, were coinjected into the pronucleus. In the second approach, both transgenes were cloned into one vector, separated by an internal ribosomal entry site (IRES), and placed under control of a single promoter. Both strategies save time and increase the percentage of double transgenic offspring over the standard method of mating single transgenic lines. However, despite high transgene copy numbers, the bicistronic lines did not show robust expression of either protein. Copy number and protein expression correlated much better in the coinjected lines, with expression levels in one line approaching that observed in some of our best single transgenic controls. Thus we recommend coinjection of individual plasmids for the generation of multiply transgenic founders.

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Author and article information

Contributors

Ming Xiao: mingx@njmu.edu.cn

Journal

Journal ID (nlm-ta): Mol Neurodegener

Journal ID (iso-abbrev): Mol Neurodegener

Title: Molecular Neurodegeneration

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1326

Publication date (Electronic): 2 November 2015

Publication date PMC-release: 2 November 2015

Publication date Collection: 2015

Volume: 10

Electronic Location Identifier: 58

Affiliations

[ ]Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029 China

[ ]Department of Rehabilitation Sciences, University of Kentucky Center of Excellence in Rural Health, Hazard, KY USA

[ ]Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei China

[ ]Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu China

Article

Publisher ID: 56

DOI: 10.1186/s13024-015-0056-1

PMC ID: 4631089

PubMed ID: 26526066

SO-VID: 9892a8f0-4c86-45a4-8cf1-d342e354d44b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 July 2015

Date accepted : 29 October 2015

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: alzheimer’s disease,amyloid-beta,astrocytes,aqp4,paravascular pathway

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: alzheimer’s disease, amyloid-beta, astrocytes, aqp4, paravascular pathway

Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits

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Abstract

Background

Results

Conclusions

Electronic supplementary material

Related collections

Functional role of amyloid

Most cited references 48

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

Interleukin-6, a Major Cytokine in the Central Nervous System

Co-expression of multiple transgenes in mouse CNS: a comparison of strategies.

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