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Beneficial effects of a pyrroloquinolinequinone-containing dietary formulation on motor deficiency, cognitive decline and mitochondrial dysfunction in a mouse model of Alzheimer ’ s disease

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP) proteolysis, tau hyperphosphorylation and the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT). A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore, in the present study, we tested the beneficial effect of a nutraceutical formulation Nutrastem II (Nutra II), containing NT020 (a mitochondrial restorative and antioxidant proprietary formulation) and pyrroloquinolinequinone (PQQ, a stimulator of mitochondria biogenesis) in 5XFAD transgenic mice. Animals were fed Nutra II for 12 weeks, starting at 3 months of age, after which behavioral and neuropathological endpoints were determined. The data from behavioral test batteries clearly revealed that dietary supplementation of Nutra II effectively ameliorated the motor deficiency and cognitive impairment of 5XFAD mice. In addition, Nutra II also protected mitochondrial function in 5XFAD mice brain, as evidenced by declined ROS levels and membrane hyperpolarization, together with elevated ATP levels and respiratory states. Interestingly, while Nutra II treatment only slightly reduced soluble Aβ42 levels, this formulation significantly impacted tau metabolism, as shown by reduced total and phosphorylated tau levels of 5XFAD mouse brain. Taken together, these preclinical findings confirm that mitochondrial function may be a key treatment target for AD and that Nutra II should be further investigated as a potential candidate for AD therapy.

No MeSH data available.


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Nutra II slightly decreases levels of Aβ, β-CTF, and Aβ plaque deposition in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of holo APP, sAPPα, β-CTF, Aβs and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD mice were also sacrificed for analysis as control. Representative WB shows holo APP, as determined by pAb751/770, sAPPα, as determined by 6E10, β-CTF and Aβ, as determined by 82E1, and β-actin, as determined by β-actin specific antibodies in triplicate (a). Full non-adjusted images of WB shown in Fig. S1 (Fig. S1.pdf). The band density was calculated by using Image J (b). Aβ1-40/42 concentrations in mouse brain homogenates from Nutra II treated and untreated 5XFAD mice were also determined by ELISA (c). Aβ plaques in hippocampal (H), entorhinal cortex (EC) and retrosplenial cortex (RSC) was examined by immunohistochemistry staining using 4G8 (d).
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fig0035: Nutra II slightly decreases levels of Aβ, β-CTF, and Aβ plaque deposition in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of holo APP, sAPPα, β-CTF, Aβs and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD mice were also sacrificed for analysis as control. Representative WB shows holo APP, as determined by pAb751/770, sAPPα, as determined by 6E10, β-CTF and Aβ, as determined by 82E1, and β-actin, as determined by β-actin specific antibodies in triplicate (a). Full non-adjusted images of WB shown in Fig. S1 (Fig. S1.pdf). The band density was calculated by using Image J (b). Aβ1-40/42 concentrations in mouse brain homogenates from Nutra II treated and untreated 5XFAD mice were also determined by ELISA (c). Aβ plaques in hippocampal (H), entorhinal cortex (EC) and retrosplenial cortex (RSC) was examined by immunohistochemistry staining using 4G8 (d).

Mentions: While WB analysis indicates that Nutra II treatment did not significantly decrease the levels of Aβ (p = 0.08) or β-CTF (p > 0.05) in the brain of 5XFAD mice (Fig. 7a, b), the ELISA data suggested a slight decrease in soluble Aβ42 production (p < 0.05, Fig. 7c). Likewise, 12-weeks dietary supplement with Nutra II slightly ameliorated the deposition of amyloid plaques in those important brain regions for memory, including hippocampus (H), entorhinal cortex (EC) and retrosplenial cortex (RSC), as determined by immunohistochemistry (Fig. 7d). Consistently, Nutra II increased α-cleavage of APP, as evidenced by significantly increased sAPPα level (P < 0.05, Fig. 7a, b). In addition, Nutra II treatment also reduced the levels of both total and phosphorylated tau protein (Fig. 8). Therefore, the improvement of working memory elicited by Nutra II seems related to the slightly decreased levels of Aβ, β-CTF, amyloid plaques and tau, and to the significantly enhanced sAPPα levels.


Beneficial effects of a pyrroloquinolinequinone-containing dietary formulation on motor deficiency, cognitive decline and mitochondrial dysfunction in a mouse model of Alzheimer ’ s disease
Nutra II slightly decreases levels of Aβ, β-CTF, and Aβ plaque deposition in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of holo APP, sAPPα, β-CTF, Aβs and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD mice were also sacrificed for analysis as control. Representative WB shows holo APP, as determined by pAb751/770, sAPPα, as determined by 6E10, β-CTF and Aβ, as determined by 82E1, and β-actin, as determined by β-actin specific antibodies in triplicate (a). Full non-adjusted images of WB shown in Fig. S1 (Fig. S1.pdf). The band density was calculated by using Image J (b). Aβ1-40/42 concentrations in mouse brain homogenates from Nutra II treated and untreated 5XFAD mice were also determined by ELISA (c). Aβ plaques in hippocampal (H), entorhinal cortex (EC) and retrosplenial cortex (RSC) was examined by immunohistochemistry staining using 4G8 (d).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5384415&req=5

fig0035: Nutra II slightly decreases levels of Aβ, β-CTF, and Aβ plaque deposition in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of holo APP, sAPPα, β-CTF, Aβs and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD mice were also sacrificed for analysis as control. Representative WB shows holo APP, as determined by pAb751/770, sAPPα, as determined by 6E10, β-CTF and Aβ, as determined by 82E1, and β-actin, as determined by β-actin specific antibodies in triplicate (a). Full non-adjusted images of WB shown in Fig. S1 (Fig. S1.pdf). The band density was calculated by using Image J (b). Aβ1-40/42 concentrations in mouse brain homogenates from Nutra II treated and untreated 5XFAD mice were also determined by ELISA (c). Aβ plaques in hippocampal (H), entorhinal cortex (EC) and retrosplenial cortex (RSC) was examined by immunohistochemistry staining using 4G8 (d).
Mentions: While WB analysis indicates that Nutra II treatment did not significantly decrease the levels of Aβ (p = 0.08) or β-CTF (p > 0.05) in the brain of 5XFAD mice (Fig. 7a, b), the ELISA data suggested a slight decrease in soluble Aβ42 production (p < 0.05, Fig. 7c). Likewise, 12-weeks dietary supplement with Nutra II slightly ameliorated the deposition of amyloid plaques in those important brain regions for memory, including hippocampus (H), entorhinal cortex (EC) and retrosplenial cortex (RSC), as determined by immunohistochemistry (Fig. 7d). Consistently, Nutra II increased α-cleavage of APP, as evidenced by significantly increased sAPPα level (P < 0.05, Fig. 7a, b). In addition, Nutra II treatment also reduced the levels of both total and phosphorylated tau protein (Fig. 8). Therefore, the improvement of working memory elicited by Nutra II seems related to the slightly decreased levels of Aβ, β-CTF, amyloid plaques and tau, and to the significantly enhanced sAPPα levels.

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer&rsquo;s disease (AD), a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP) proteolysis, tau hyperphosphorylation and the accumulation of amyloid-&beta; (A&beta;) plaques and neurofibrillary tangles (NFT). A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore, in the present study, we tested the beneficial effect of a nutraceutical formulation Nutrastem II (Nutra II), containing NT020 (a mitochondrial restorative and antioxidant proprietary formulation) and pyrroloquinolinequinone (PQQ, a stimulator of mitochondria biogenesis) in 5XFAD transgenic mice. Animals were fed Nutra II for 12 weeks, starting at 3 months of age, after which behavioral and neuropathological endpoints were determined. The data from behavioral test batteries clearly revealed that dietary supplementation of Nutra II effectively ameliorated the motor deficiency and cognitive impairment of 5XFAD mice. In addition, Nutra II also protected mitochondrial function in 5XFAD mice brain, as evidenced by declined ROS levels and membrane hyperpolarization, together with elevated ATP levels and respiratory states. Interestingly, while Nutra II treatment only slightly reduced soluble A&beta;42 levels, this formulation significantly impacted tau metabolism, as shown by reduced total and phosphorylated tau levels of 5XFAD mouse brain. Taken together, these preclinical findings confirm that mitochondrial function may be a key treatment target for AD and that Nutra II should be further investigated as a potential candidate for AD therapy.

No MeSH data available.


Related in: MedlinePlus