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

Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T, Hu G, Xiao M - Mol Neurodegener (2015)

Bottom Line: However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent.Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignificant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples.These results suggest that AQP4 attenuates Aβ pathogenesis despite its potentially inflammatory side-effects, thus serving as a promising target for treating AD.

View Article: PubMed Central - PubMed

Affiliation: Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.

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 nonsignificant 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.

No MeSH data available.


Related in: MedlinePlus

AQP4 deficiency increased brain Aβ accumulation and CAA in 12 month-old APP/PS1 mice. a Aβ deposition in the hippocampus and cortex stained by 6E10 and Thioflavin-S. b High magnification micrographs of 6E10 immunostaining. There was increased amyloid deposition along small and large vessels in the brain parenchyma (arrowheads) and leptomeningeal vessels (stars) of AQP4−/−APP/PS1 mice, compared to APP/PS1 controls. c The area percentage of 6E10-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. d The area percentage of Thioflavin-S-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. e 6E10-immunoreactive (IR) intensity on the cortical vessels and leptomeningeal vessels. f-i ELISA analysis of soluble and insoluble Aβ1–40 and Aβ1–42 in the brain samples. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by Student’s t-test. *P < 0.05; **P < 0.01; ***P < 0.001
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Fig2: AQP4 deficiency increased brain Aβ accumulation and CAA in 12 month-old APP/PS1 mice. a Aβ deposition in the hippocampus and cortex stained by 6E10 and Thioflavin-S. b High magnification micrographs of 6E10 immunostaining. There was increased amyloid deposition along small and large vessels in the brain parenchyma (arrowheads) and leptomeningeal vessels (stars) of AQP4−/−APP/PS1 mice, compared to APP/PS1 controls. c The area percentage of 6E10-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. d The area percentage of Thioflavin-S-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. e 6E10-immunoreactive (IR) intensity on the cortical vessels and leptomeningeal vessels. f-i ELISA analysis of soluble and insoluble Aβ1–40 and Aβ1–42 in the brain samples. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by Student’s t-test. *P < 0.05; **P < 0.01; ***P < 0.001

Mentions: The previous study revealed that AQP4 deficiency impairs the clearance of intraparenchymal injection of exogenous Aβ peptide [5]. In the present study, we addressed the long-term contribution of AQP4 to the clearance of endogenous Aβ in APP/PS1 mouse brain. In 12-month old AQP4−/−APP/PS1 mice, Thioflavin-S positive fibrillar plaques and 6E10-immunopositive diffuse plaques occupied a great deal of the hippocampal and cortical areas, compared to APP/PS1 mice (Fig. 2a, c, d). In addition to the brain parenchyma, Aβ deposition manifested in cortical and leptomeningeal vessels as cerebral amyloid angiopathy (CAA), which was also increased in the AQP4−/−APP/PS1 mice (Fig. 2b, e). Consistent with increased amyloid load, ELISA analysis demonstrated that AQP4 deficiency increased both soluble and insoluble Aβ1–40 and Aβ1–42 levels in APP/PS1 mouse brain (Fig. 2f-i).Fig. 2


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

Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T, Hu G, Xiao M - Mol Neurodegener (2015)

AQP4 deficiency increased brain Aβ accumulation and CAA in 12 month-old APP/PS1 mice. a Aβ deposition in the hippocampus and cortex stained by 6E10 and Thioflavin-S. b High magnification micrographs of 6E10 immunostaining. There was increased amyloid deposition along small and large vessels in the brain parenchyma (arrowheads) and leptomeningeal vessels (stars) of AQP4−/−APP/PS1 mice, compared to APP/PS1 controls. c The area percentage of 6E10-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. d The area percentage of Thioflavin-S-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. e 6E10-immunoreactive (IR) intensity on the cortical vessels and leptomeningeal vessels. f-i ELISA analysis of soluble and insoluble Aβ1–40 and Aβ1–42 in the brain samples. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by Student’s t-test. *P < 0.05; **P < 0.01; ***P < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4631089&req=5

Fig2: AQP4 deficiency increased brain Aβ accumulation and CAA in 12 month-old APP/PS1 mice. a Aβ deposition in the hippocampus and cortex stained by 6E10 and Thioflavin-S. b High magnification micrographs of 6E10 immunostaining. There was increased amyloid deposition along small and large vessels in the brain parenchyma (arrowheads) and leptomeningeal vessels (stars) of AQP4−/−APP/PS1 mice, compared to APP/PS1 controls. c The area percentage of 6E10-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. d The area percentage of Thioflavin-S-positive Aβ plaque load in the hippocampus (HC) and cerebral cortex. e 6E10-immunoreactive (IR) intensity on the cortical vessels and leptomeningeal vessels. f-i ELISA analysis of soluble and insoluble Aβ1–40 and Aβ1–42 in the brain samples. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by Student’s t-test. *P < 0.05; **P < 0.01; ***P < 0.001
Mentions: The previous study revealed that AQP4 deficiency impairs the clearance of intraparenchymal injection of exogenous Aβ peptide [5]. In the present study, we addressed the long-term contribution of AQP4 to the clearance of endogenous Aβ in APP/PS1 mouse brain. In 12-month old AQP4−/−APP/PS1 mice, Thioflavin-S positive fibrillar plaques and 6E10-immunopositive diffuse plaques occupied a great deal of the hippocampal and cortical areas, compared to APP/PS1 mice (Fig. 2a, c, d). In addition to the brain parenchyma, Aβ deposition manifested in cortical and leptomeningeal vessels as cerebral amyloid angiopathy (CAA), which was also increased in the AQP4−/−APP/PS1 mice (Fig. 2b, e). Consistent with increased amyloid load, ELISA analysis demonstrated that AQP4 deficiency increased both soluble and insoluble Aβ1–40 and Aβ1–42 levels in APP/PS1 mouse brain (Fig. 2f-i).Fig. 2

Bottom Line: However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent.Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignificant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples.These results suggest that AQP4 attenuates Aβ pathogenesis despite its potentially inflammatory side-effects, thus serving as a promising target for treating AD.

View Article: PubMed Central - PubMed

Affiliation: Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.

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 nonsignificant 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.

No MeSH data available.


Related in: MedlinePlus