Limits...
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.


Nutra II reduces levels of total and phosphorylated tau in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of phosphorylated tau, total tau and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD and WT mice were also sacrificed as controls. Representative WB shows PHF1, as determined by p-tau231, total tau, as determined by tau46, and β-actin as determined by β-actin specific antibodies in duplicate (WT) or triplicate (5XFAD/Ctrl and 5XFAD/Nutra II, a). Full non-adjusted images of WB shown in Fig. S2 (Fig. S2.pdf). PHF1 immunoreactivity was increased in 5XFAD mice in comparison with WT mice and PHF1 and total tau immunoreactivities were reduced after Nutra II treatment in 5XFAD mice in comparison with untreated 5XFAD mice (a, upper panel). Representative WB shows phospho-tau (AT270), as determined by p-tau181, and β-actin in Nutra II treated and untreated 5XFAD mice in triplicate, confirming that Nutra II reduces phospho-tau in this AD mouse model (c). The bands density were calculated using Image J (b & d).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384415&req=5

fig0040: Nutra II reduces levels of total and phosphorylated tau in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of phosphorylated tau, total tau and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD and WT mice were also sacrificed as controls. Representative WB shows PHF1, as determined by p-tau231, total tau, as determined by tau46, and β-actin as determined by β-actin specific antibodies in duplicate (WT) or triplicate (5XFAD/Ctrl and 5XFAD/Nutra II, a). Full non-adjusted images of WB shown in Fig. S2 (Fig. S2.pdf). PHF1 immunoreactivity was increased in 5XFAD mice in comparison with WT mice and PHF1 and total tau immunoreactivities were reduced after Nutra II treatment in 5XFAD mice in comparison with untreated 5XFAD mice (a, upper panel). Representative WB shows phospho-tau (AT270), as determined by p-tau181, and β-actin in Nutra II treated and untreated 5XFAD mice in triplicate, confirming that Nutra II reduces phospho-tau in this AD mouse model (c). The bands density were calculated using Image J (b & 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 reduces levels of total and phosphorylated tau in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of phosphorylated tau, total tau and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD and WT mice were also sacrificed as controls. Representative WB shows PHF1, as determined by p-tau231, total tau, as determined by tau46, and β-actin as determined by β-actin specific antibodies in duplicate (WT) or triplicate (5XFAD/Ctrl and 5XFAD/Nutra II, a). Full non-adjusted images of WB shown in Fig. S2 (Fig. S2.pdf). PHF1 immunoreactivity was increased in 5XFAD mice in comparison with WT mice and PHF1 and total tau immunoreactivities were reduced after Nutra II treatment in 5XFAD mice in comparison with untreated 5XFAD mice (a, upper panel). Representative WB shows phospho-tau (AT270), as determined by p-tau181, and β-actin in Nutra II treated and untreated 5XFAD mice in triplicate, confirming that Nutra II reduces phospho-tau in this AD mouse model (c). The bands density were calculated using Image J (b & d).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig0040: Nutra II reduces levels of total and phosphorylated tau in 5XFAD mice - After Nutra II treatment, 5XFAD mice were sacrificed for analysis of phosphorylated tau, total tau and β-actin as control in brain homogenates using WB analysis. Untreated 5XFAD and WT mice were also sacrificed as controls. Representative WB shows PHF1, as determined by p-tau231, total tau, as determined by tau46, and β-actin as determined by β-actin specific antibodies in duplicate (WT) or triplicate (5XFAD/Ctrl and 5XFAD/Nutra II, a). Full non-adjusted images of WB shown in Fig. S2 (Fig. S2.pdf). PHF1 immunoreactivity was increased in 5XFAD mice in comparison with WT mice and PHF1 and total tau immunoreactivities were reduced after Nutra II treatment in 5XFAD mice in comparison with untreated 5XFAD mice (a, upper panel). Representative WB shows phospho-tau (AT270), as determined by p-tau181, and β-actin in Nutra II treated and untreated 5XFAD mice in triplicate, confirming that Nutra II reduces phospho-tau in this AD mouse model (c). The bands density were calculated using Image J (b & 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.