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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.


Related in: MedlinePlus

Nutra II improves hippocampal-dependent learning and memory - The cognitive function of 5XFAD mice was assessed using Morris water maze (a-c), Y-maze (d-e) and fear conditioning test (f-g). In the Morris water maze test, 5XFAD mice untreated displayed an increased latency to find the platform (a), decreased swimming speed (b) and a decreased time spent in the target quadrant compared with WT mice (c), which was reversed with Nutra II treatment (**P < 0.01 versus untreated). Consistent with Morris water maze test, levels of spontaneous alternation in Y-maze were significantly lower in untreated 5XFAD mice compared with WT mice, and this impairment was reversed with Nutra II treatment (*P < 0.05). The impaired cognitive function and the reversal effect of Nutra II were also assessed by using fear conditioning test. 5XFAD mice treated with Nutra II showed increased levels of freezing in response to both conditioned stimulus or context compared to 5XFAD untreated mice (*P < 0.05).
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fig0030: Nutra II improves hippocampal-dependent learning and memory - The cognitive function of 5XFAD mice was assessed using Morris water maze (a-c), Y-maze (d-e) and fear conditioning test (f-g). In the Morris water maze test, 5XFAD mice untreated displayed an increased latency to find the platform (a), decreased swimming speed (b) and a decreased time spent in the target quadrant compared with WT mice (c), which was reversed with Nutra II treatment (**P < 0.01 versus untreated). Consistent with Morris water maze test, levels of spontaneous alternation in Y-maze were significantly lower in untreated 5XFAD mice compared with WT mice, and this impairment was reversed with Nutra II treatment (*P < 0.05). The impaired cognitive function and the reversal effect of Nutra II were also assessed by using fear conditioning test. 5XFAD mice treated with Nutra II showed increased levels of freezing in response to both conditioned stimulus or context compared to 5XFAD untreated mice (*P < 0.05).

Mentions: To assess hippocampal-dependent learning and memory, 5XFAD and WT control mice were tested in the hidden-platform Morris water maze and Y maze tasks. With the Morris water task, untreated 5XFAD mice displayed an increase in escape latency to find the hidden platform during training between trials 8 and 12 compared to WT mice (Fig. 6a). This increase was reversed after treatment with Nutra II. Likewise, during the probe trial, untreated 5XFAD mice displayed a decreased time spent in the target quadrant compared with WT mice, which again was reversed with Nutra II treatment (Fig. 6c). Consistent with rotarod test, EPM and OF test, 5XFAD mice also showed a declined motor ability in MWM test, as indicated by a gradually decreased swimming speed (Fig. 6b). As expected, this motor deficiency can be ameliorated by Nutra II treatment. In the Y maze test, levels of spontaneous alternation were significantly lower in untreated 5XFAD mice compared with WT mice, and this impairment was reversed by Nutra II treatment (Fig. 6d). These results further support a role for Nutra II to improve hippocampal-dependent learning and memory in 5XFAD mice. Latency for first exit from the starting arm was increased in untreated 5XFAD mice compared with WT mice, confirming a reduced exploratory and risk assessment behavior in this AD mouse model (Fig. 6e). This deficiency of risk assessment behavior was unaltered by Nutra II treatment.


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 improves hippocampal-dependent learning and memory - The cognitive function of 5XFAD mice was assessed using Morris water maze (a-c), Y-maze (d-e) and fear conditioning test (f-g). In the Morris water maze test, 5XFAD mice untreated displayed an increased latency to find the platform (a), decreased swimming speed (b) and a decreased time spent in the target quadrant compared with WT mice (c), which was reversed with Nutra II treatment (**P < 0.01 versus untreated). Consistent with Morris water maze test, levels of spontaneous alternation in Y-maze were significantly lower in untreated 5XFAD mice compared with WT mice, and this impairment was reversed with Nutra II treatment (*P < 0.05). The impaired cognitive function and the reversal effect of Nutra II were also assessed by using fear conditioning test. 5XFAD mice treated with Nutra II showed increased levels of freezing in response to both conditioned stimulus or context compared to 5XFAD untreated mice (*P < 0.05).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig0030: Nutra II improves hippocampal-dependent learning and memory - The cognitive function of 5XFAD mice was assessed using Morris water maze (a-c), Y-maze (d-e) and fear conditioning test (f-g). In the Morris water maze test, 5XFAD mice untreated displayed an increased latency to find the platform (a), decreased swimming speed (b) and a decreased time spent in the target quadrant compared with WT mice (c), which was reversed with Nutra II treatment (**P < 0.01 versus untreated). Consistent with Morris water maze test, levels of spontaneous alternation in Y-maze were significantly lower in untreated 5XFAD mice compared with WT mice, and this impairment was reversed with Nutra II treatment (*P < 0.05). The impaired cognitive function and the reversal effect of Nutra II were also assessed by using fear conditioning test. 5XFAD mice treated with Nutra II showed increased levels of freezing in response to both conditioned stimulus or context compared to 5XFAD untreated mice (*P < 0.05).
Mentions: To assess hippocampal-dependent learning and memory, 5XFAD and WT control mice were tested in the hidden-platform Morris water maze and Y maze tasks. With the Morris water task, untreated 5XFAD mice displayed an increase in escape latency to find the hidden platform during training between trials 8 and 12 compared to WT mice (Fig. 6a). This increase was reversed after treatment with Nutra II. Likewise, during the probe trial, untreated 5XFAD mice displayed a decreased time spent in the target quadrant compared with WT mice, which again was reversed with Nutra II treatment (Fig. 6c). Consistent with rotarod test, EPM and OF test, 5XFAD mice also showed a declined motor ability in MWM test, as indicated by a gradually decreased swimming speed (Fig. 6b). As expected, this motor deficiency can be ameliorated by Nutra II treatment. In the Y maze test, levels of spontaneous alternation were significantly lower in untreated 5XFAD mice compared with WT mice, and this impairment was reversed by Nutra II treatment (Fig. 6d). These results further support a role for Nutra II to improve hippocampal-dependent learning and memory in 5XFAD mice. Latency for first exit from the starting arm was increased in untreated 5XFAD mice compared with WT mice, confirming a reduced exploratory and risk assessment behavior in this AD mouse model (Fig. 6e). This deficiency of risk assessment behavior was unaltered by Nutra II treatment.

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