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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 exacerbated decreases in SYP and PSD-95 in 12-month-old APP/PS1 mice. a SYP and PSD-95 expression was markedly decreased in the hippocampus and cerebral cortex of AQP4−/−APP/PS1 mice, compared to APP/PS1 mice. b The percentage of SYP/PSD-95 positive area in the hippocampus and cortex. c Representative bands of Western bolt and d densitometry analysis of SYP and PSD-95 protein levels in the hippocampus and cortex. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by ANOVA with post hoc Student-Newman-Keuls test. *P < 0.05; **P < 0.01; ***P < 0.001
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Fig6: AQP4 deficiency exacerbated decreases in SYP and PSD-95 in 12-month-old APP/PS1 mice. a SYP and PSD-95 expression was markedly decreased in the hippocampus and cerebral cortex of AQP4−/−APP/PS1 mice, compared to APP/PS1 mice. b The percentage of SYP/PSD-95 positive area in the hippocampus and cortex. c Representative bands of Western bolt and d densitometry analysis of SYP and PSD-95 protein levels in the hippocampus and cortex. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by ANOVA with post hoc Student-Newman-Keuls test. *P < 0.05; **P < 0.01; ***P < 0.001

Mentions: Synaptic impairment in the hippocampus and cerebral cortex is a main pathological basis for cognitive impairment in AD [2]. Both synaptophysin (SYP) and post-synaptic density protein-95 (PSD-95) are particularly vulnerable to the toxic effects of Αβ, and their loss correlates with cognitive decline in AD [34–36]. Therefore, we determined whether genetic deletion of AQP4 in APP/PS1 mice advanced cognitive impairment was associated with more severe impairment of SYP and PSD-95. Deletion of AQP4 in 12-month old APP/PS1 mice significantly exacerbated loss of SYP and PSD-95 in the hippocampus and cerebral cortex as revealed by both immunohistochemistry (Fig. 6a, b) and Western blot analyses (Fig. 6c, d).Fig. 6


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 exacerbated decreases in SYP and PSD-95 in 12-month-old APP/PS1 mice. a SYP and PSD-95 expression was markedly decreased in the hippocampus and cerebral cortex of AQP4−/−APP/PS1 mice, compared to APP/PS1 mice. b The percentage of SYP/PSD-95 positive area in the hippocampus and cortex. c Representative bands of Western bolt and d densitometry analysis of SYP and PSD-95 protein levels in the hippocampus and cortex. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by ANOVA with post hoc Student-Newman-Keuls 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

Fig6: AQP4 deficiency exacerbated decreases in SYP and PSD-95 in 12-month-old APP/PS1 mice. a SYP and PSD-95 expression was markedly decreased in the hippocampus and cerebral cortex of AQP4−/−APP/PS1 mice, compared to APP/PS1 mice. b The percentage of SYP/PSD-95 positive area in the hippocampus and cortex. c Representative bands of Western bolt and d densitometry analysis of SYP and PSD-95 protein levels in the hippocampus and cortex. Data represent mean ± SEM from 5 to 6 mice (3–4 female, and 1–2 male) per group. The statistical analysis was performed by ANOVA with post hoc Student-Newman-Keuls test. *P < 0.05; **P < 0.01; ***P < 0.001
Mentions: Synaptic impairment in the hippocampus and cerebral cortex is a main pathological basis for cognitive impairment in AD [2]. Both synaptophysin (SYP) and post-synaptic density protein-95 (PSD-95) are particularly vulnerable to the toxic effects of Αβ, and their loss correlates with cognitive decline in AD [34–36]. Therefore, we determined whether genetic deletion of AQP4 in APP/PS1 mice advanced cognitive impairment was associated with more severe impairment of SYP and PSD-95. Deletion of AQP4 in 12-month old APP/PS1 mice significantly exacerbated loss of SYP and PSD-95 in the hippocampus and cerebral cortex as revealed by both immunohistochemistry (Fig. 6a, b) and Western blot analyses (Fig. 6c, d).Fig. 6

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