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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 did not alter expression of brain Aβ formation and degradation-related proteins in 12 month-old APP/PS1 mice. a Representative bands of Western bolt and b densitometry analysis of protein levels of APP and its proteolytic amyloidogenic fragments. c Representative bands of Western bolt and d densitometry analysis of protein levels of the biochemical components involved in the amyloid production (BACE1 and PS1) and degradation (IDE and NEP). 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
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Fig3: AQP4 deficiency did not alter expression of brain Aβ formation and degradation-related proteins in 12 month-old APP/PS1 mice. a Representative bands of Western bolt and b densitometry analysis of protein levels of APP and its proteolytic amyloidogenic fragments. c Representative bands of Western bolt and d densitometry analysis of protein levels of the biochemical components involved in the amyloid production (BACE1 and PS1) and degradation (IDE and NEP). 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

Mentions: To further investigate the molecular mechanisms of the effects of AQP4 deficiency on plaque pathogenesis, we examined the expression of proteins involved in Aβ synthesis and degradation in the cerebral cortex and hippocampus lysates. APP is processed first by the β-secretase (β-site amyloid precursor protein-cleaving enzyme 1, BACE1) to form the soluble peptide APP β (SAPPβ), and transmembrane peptide C-terminal fragments (CTFβ) [22]. The latter are cleaved by the γ-secretase complex, including presenilin 1 (PS1), to form Aβ peptides, which are subsequently released into the extracellular space [22]. AQP4−/−APP/PS1 mice demonstrated significant increases in levels of Aβ1–42 and SAPPβ, but no significant changes in APP, CTFβ, BACE1 and PS1 (Fig. 3a-d), suggesting that AQP4 gene deletion did not affect APP production and processing, but selectively impaired clearance of its soluble proteolytic fragments from the brain. In addition, insulin degrading enzyme (IDE) and neprilysin (NEP), the two major Aβ-degrading enzymes in the brain [23], showed no significant changes in AQP4−/−APP/PS1 mice (Fig. 3c, d) (Additional file 1: Figure S1). Taken together, these data indicate that AQP4 deficiency could be impair rapid transport of water-mediated Aβ clearance from the brain parenchyma, subsequently increasing the Aβ burden in APP/PS1 mouse brain without altering the expression levels of Aβ formation and degradation-related proteins.Fig. 3


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 did not alter expression of brain Aβ formation and degradation-related proteins in 12 month-old APP/PS1 mice. a Representative bands of Western bolt and b densitometry analysis of protein levels of APP and its proteolytic amyloidogenic fragments. c Representative bands of Western bolt and d densitometry analysis of protein levels of the biochemical components involved in the amyloid production (BACE1 and PS1) and degradation (IDE and NEP). 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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: AQP4 deficiency did not alter expression of brain Aβ formation and degradation-related proteins in 12 month-old APP/PS1 mice. a Representative bands of Western bolt and b densitometry analysis of protein levels of APP and its proteolytic amyloidogenic fragments. c Representative bands of Western bolt and d densitometry analysis of protein levels of the biochemical components involved in the amyloid production (BACE1 and PS1) and degradation (IDE and NEP). 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
Mentions: To further investigate the molecular mechanisms of the effects of AQP4 deficiency on plaque pathogenesis, we examined the expression of proteins involved in Aβ synthesis and degradation in the cerebral cortex and hippocampus lysates. APP is processed first by the β-secretase (β-site amyloid precursor protein-cleaving enzyme 1, BACE1) to form the soluble peptide APP β (SAPPβ), and transmembrane peptide C-terminal fragments (CTFβ) [22]. The latter are cleaved by the γ-secretase complex, including presenilin 1 (PS1), to form Aβ peptides, which are subsequently released into the extracellular space [22]. AQP4−/−APP/PS1 mice demonstrated significant increases in levels of Aβ1–42 and SAPPβ, but no significant changes in APP, CTFβ, BACE1 and PS1 (Fig. 3a-d), suggesting that AQP4 gene deletion did not affect APP production and processing, but selectively impaired clearance of its soluble proteolytic fragments from the brain. In addition, insulin degrading enzyme (IDE) and neprilysin (NEP), the two major Aβ-degrading enzymes in the brain [23], showed no significant changes in AQP4−/−APP/PS1 mice (Fig. 3c, d) (Additional file 1: Figure S1). Taken together, these data indicate that AQP4 deficiency could be impair rapid transport of water-mediated Aβ clearance from the brain parenchyma, subsequently increasing the Aβ burden in APP/PS1 mouse brain without altering the expression levels of Aβ formation and degradation-related proteins.Fig. 3

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