Journal: Canadian Journal of Zoology Manuscript ID cjz-2016-0243.R1 Manuscript Type: Article Date... more Journal: Canadian Journal of Zoology Manuscript ID cjz-2016-0243.R1 Manuscript Type: Article Date Submitted by the Author: 28-Feb-2017 Complete List of Authors: Adlimoghaddam, Aida; University of Manitoba, Biological Sciences O`Donnell, Michael; McMaster University Quijada-Rodriguez, Alex; University of Manitoba, Biological Sciences Weihrauch, Dirk; University of Manitoba, Biological Sciences; University of Manitoba, Biological Sciences Keyword: Amiloride, EIPA, SIET, NHE, Na+-channel, C. elegans, Nematode
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that redu... more Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators ...
The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reduct... more The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enha...
The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types o... more The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammatio...
Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure... more Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including amyloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflamm...
Current treatments targeting amyloid beta in Alzheimer's disease (AD) have minimal effica... more Current treatments targeting amyloid beta in Alzheimer's disease (AD) have minimal efficacy, which results in a huge unmet medical need worldwide. Accumulating data suggest that brain mitochondrial dysfunction play a critical role in AD pathogenesis. Targeting cellular mechanisms associated with mitochondrial dysfunction in AD create a novel approach for drug development. This study investigated the effects of nilotinib, as a selective tyrosine kinase inhibitor, in astroglia derived from 3xTg-AD mice versus their C57BL/6-controls. Parameters included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX), citrate synthase (CS) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-κB), key regulators of mitochondrial dynamics (mitofusin (Mfn1), dynamin-related protein 1 (Drp1)), and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), calcium/calmodulin-dependent protein kinase II (CaMKII), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)). Nilotinib increased OCR, ATP, COX, Mfn1, and OXPHOS levels in 3xTg astroglia. No significant differences were detected in levels of Drp1 protein and CS activity. Nilotinib enhanced mitochondrial numbers, potentially through a CaMKII-PGC1α-Nrf2 pathway in 3xTg astroglia. Additionally, nilotinib-induced OCR increases were reduced in the presence of the NF-κB inhibitor, Bay11-7082. The data suggest that NF-κB signaling is intimately involved in nilotinib-induced changes in bioenergetics in 3xTg brain astroglia. Nilotinib increased translocation of the NF-κB p50 subunit into the nucleus of 3xTg astroglia that correlates with an increased expression and activation of NF-κB. The current findings support a role for nilotinib in improving mitochondrial function and suggest that astroglia may be a key therapeutic target in treating AD.
Dementia is a growing public health concern in Canada. This epidemic is linked to huge human and ... more Dementia is a growing public health concern in Canada. This epidemic is linked to huge human and economic costs. The number of Manitobans (65+) with dementia in 2045 (47,021), representing 2.58% of the Manitoban population, will be 2.3 times that of the year 2015 (20,235). The number of cases of dementia in Manitoba grew by 20.7% from 2015 to 2025, 68.16% from 2015 to 2035 and at an alarming rate of 125% from 2015 to 2045. Importantly, the total economic burden of dementia in Manitoba is close to one billion USD and is expected to grow more than 28 billion USD during the year 2038. The focus of this review is to compare dementia rates and the financial burden of dementia in Manitoba with the rest of Canada and the world from 2012 to 2048.
Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people ... more Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people worldwide. Patients with severe AD require help with daily activities and show severe memory impairment. Currently, donepezil is one of two drugs approved by FDA and Health Canada for the treatment of severe AD (MMSE score <10). It is prescribed as 5 or 10 mg/d and an FDA-approved 23-mg/d dose. This review will discuss risks and benefits of donepezil at these doses in severe AD. Articles were identified using PubMed using the MeSH terms "donepezil" AND "Alzheimer Disease" AND "severe." Three double-blind, placebo-controlled, randomized studies, one post hoc analysis, and one subgroup analysis were selected. Donepezil was found to benefit patients in cognition and global functioning. The most consistent improvement was in severe impairment battery (SIB) scores. However, more patients treated with high dosage of donepezil discontinued their treatment due to...
Cation/proton exchangers of the cation proton antiporter 1 (CPA1) subfamily (NHEs, SLC 9) play an... more Cation/proton exchangers of the cation proton antiporter 1 (CPA1) subfamily (NHEs, SLC 9) play an important role in many physiological processes, including cell volume regulation, acid–base homeostasis, and ammonia excretion. The soil nematode Caenorhabditis elegans (Maupas, 1900) (N2, 1968) expresses nine paralogues (NHX-1 to NHX-9). The current study was undertaken to investigate the role of the cation/proton exchanger in hypodermal Na+ and H+ fluxes, as well in ammonia excretion processes. Measurements using SIET (scanning ion-selective electrode technique) showed that the hypodermis promotes H+ secretion and Na+ uptake. Inhibitory effects on fluxes were observed upon application of amiloride but not EIPA, suggesting that NHXs are not involved in the transport processes. In response to stress induced by starvation or exposure to 1 mmol·L−1 NH4Cl, pH 5.5, or pH 8.0, body pH stayed fairly constant, with changes in mRNA expression levels detected in intestinal NHX-2 and hypodermal N...
Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, Jan 9, 2016
Previous studies have shown the free living soil nematode Caenorhabditis elegans (N2 strain) to b... more Previous studies have shown the free living soil nematode Caenorhabditis elegans (N2 strain) to be ammonotelic. Ammonia excretion was suggested to take place partially via the hypodermis, involving the Na(+)/K(+)-ATPase (NKA), V-ATPase (VAT), carbonic anhydrase, NHX-3 and a functional microtubule network and at least one Rh-like ammonia transporter RHR-1. In the current study, we show that a second Rh-protein, RHR-2, is highly expressed in the hypodermis, here also in the apical membrane of that tissue. To further characterize the role of RHR-2 in ammonia excretion, a knock-out mutant rhr-2 (ok403), further referred to as ∆rhr-2, was employed. Compared to wild-type worms (N2), this mutant showed a lower rate of ammonia excretion and a lower hypodermal H(+) excretion rate. At the same time rhr-1, nka, vat, and nhx-3 showed higher mRNA expression levels when compared to N2. Also, in contrast to N2 worms, ∆rhr-2 did not show enhanced ammonia excretion rates when exposed to a low pH env...
The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast ... more The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast majority of its nitrogenous waste as ammonia (25.3±1.2 µmol gFW(-1) day(-1)) and very little urea (0.21±0.004 µmol gFW(-1) day(-1)). Although these roundworms have been used for decades as genetic model systems, very little is known about their strategy to eliminate the toxic waste product ammonia from their bodies into the environment. The current study provides evidence that ammonia is at least partially excreted via the hypodermis. Starvation reduced the ammonia excretion rates by more than half, whereas mRNA expression levels of the Rhesus protein CeRhr-2, V-type H(+)-ATPase (subunit A) and Na(+)/K(+)-ATPase (α-subunit) decreased correspondingly. Moreover, ammonia excretion rates were enhanced in media buffered to pH 5 and decreased at pH 9.5. Inhibitor experiments, combined with enzyme activity measurements and mRNA expression analyses, further suggested that the excretion mechanism...
Journal: Canadian Journal of Zoology Manuscript ID cjz-2016-0243.R1 Manuscript Type: Article Date... more Journal: Canadian Journal of Zoology Manuscript ID cjz-2016-0243.R1 Manuscript Type: Article Date Submitted by the Author: 28-Feb-2017 Complete List of Authors: Adlimoghaddam, Aida; University of Manitoba, Biological Sciences O`Donnell, Michael; McMaster University Quijada-Rodriguez, Alex; University of Manitoba, Biological Sciences Weihrauch, Dirk; University of Manitoba, Biological Sciences; University of Manitoba, Biological Sciences Keyword: Amiloride, EIPA, SIET, NHE, Na+-channel, C. elegans, Nematode
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that redu... more Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators ...
The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reduct... more The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enha...
The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types o... more The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammatio...
Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure... more Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including amyloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflamm...
Current treatments targeting amyloid beta in Alzheimer&#39;s disease (AD) have minimal effica... more Current treatments targeting amyloid beta in Alzheimer&#39;s disease (AD) have minimal efficacy, which results in a huge unmet medical need worldwide. Accumulating data suggest that brain mitochondrial dysfunction play a critical role in AD pathogenesis. Targeting cellular mechanisms associated with mitochondrial dysfunction in AD create a novel approach for drug development. This study investigated the effects of nilotinib, as a selective tyrosine kinase inhibitor, in astroglia derived from 3xTg-AD mice versus their C57BL/6-controls. Parameters included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX), citrate synthase (CS) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-κB), key regulators of mitochondrial dynamics (mitofusin (Mfn1), dynamin-related protein 1 (Drp1)), and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), calcium/calmodulin-dependent protein kinase II (CaMKII), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)). Nilotinib increased OCR, ATP, COX, Mfn1, and OXPHOS levels in 3xTg astroglia. No significant differences were detected in levels of Drp1 protein and CS activity. Nilotinib enhanced mitochondrial numbers, potentially through a CaMKII-PGC1α-Nrf2 pathway in 3xTg astroglia. Additionally, nilotinib-induced OCR increases were reduced in the presence of the NF-κB inhibitor, Bay11-7082. The data suggest that NF-κB signaling is intimately involved in nilotinib-induced changes in bioenergetics in 3xTg brain astroglia. Nilotinib increased translocation of the NF-κB p50 subunit into the nucleus of 3xTg astroglia that correlates with an increased expression and activation of NF-κB. The current findings support a role for nilotinib in improving mitochondrial function and suggest that astroglia may be a key therapeutic target in treating AD.
Dementia is a growing public health concern in Canada. This epidemic is linked to huge human and ... more Dementia is a growing public health concern in Canada. This epidemic is linked to huge human and economic costs. The number of Manitobans (65+) with dementia in 2045 (47,021), representing 2.58% of the Manitoban population, will be 2.3 times that of the year 2015 (20,235). The number of cases of dementia in Manitoba grew by 20.7% from 2015 to 2025, 68.16% from 2015 to 2035 and at an alarming rate of 125% from 2015 to 2045. Importantly, the total economic burden of dementia in Manitoba is close to one billion USD and is expected to grow more than 28 billion USD during the year 2038. The focus of this review is to compare dementia rates and the financial burden of dementia in Manitoba with the rest of Canada and the world from 2012 to 2048.
Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people ... more Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people worldwide. Patients with severe AD require help with daily activities and show severe memory impairment. Currently, donepezil is one of two drugs approved by FDA and Health Canada for the treatment of severe AD (MMSE score <10). It is prescribed as 5 or 10 mg/d and an FDA-approved 23-mg/d dose. This review will discuss risks and benefits of donepezil at these doses in severe AD. Articles were identified using PubMed using the MeSH terms "donepezil" AND "Alzheimer Disease" AND "severe." Three double-blind, placebo-controlled, randomized studies, one post hoc analysis, and one subgroup analysis were selected. Donepezil was found to benefit patients in cognition and global functioning. The most consistent improvement was in severe impairment battery (SIB) scores. However, more patients treated with high dosage of donepezil discontinued their treatment due to...
Cation/proton exchangers of the cation proton antiporter 1 (CPA1) subfamily (NHEs, SLC 9) play an... more Cation/proton exchangers of the cation proton antiporter 1 (CPA1) subfamily (NHEs, SLC 9) play an important role in many physiological processes, including cell volume regulation, acid–base homeostasis, and ammonia excretion. The soil nematode Caenorhabditis elegans (Maupas, 1900) (N2, 1968) expresses nine paralogues (NHX-1 to NHX-9). The current study was undertaken to investigate the role of the cation/proton exchanger in hypodermal Na+ and H+ fluxes, as well in ammonia excretion processes. Measurements using SIET (scanning ion-selective electrode technique) showed that the hypodermis promotes H+ secretion and Na+ uptake. Inhibitory effects on fluxes were observed upon application of amiloride but not EIPA, suggesting that NHXs are not involved in the transport processes. In response to stress induced by starvation or exposure to 1 mmol·L−1 NH4Cl, pH 5.5, or pH 8.0, body pH stayed fairly constant, with changes in mRNA expression levels detected in intestinal NHX-2 and hypodermal N...
Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, Jan 9, 2016
Previous studies have shown the free living soil nematode Caenorhabditis elegans (N2 strain) to b... more Previous studies have shown the free living soil nematode Caenorhabditis elegans (N2 strain) to be ammonotelic. Ammonia excretion was suggested to take place partially via the hypodermis, involving the Na(+)/K(+)-ATPase (NKA), V-ATPase (VAT), carbonic anhydrase, NHX-3 and a functional microtubule network and at least one Rh-like ammonia transporter RHR-1. In the current study, we show that a second Rh-protein, RHR-2, is highly expressed in the hypodermis, here also in the apical membrane of that tissue. To further characterize the role of RHR-2 in ammonia excretion, a knock-out mutant rhr-2 (ok403), further referred to as ∆rhr-2, was employed. Compared to wild-type worms (N2), this mutant showed a lower rate of ammonia excretion and a lower hypodermal H(+) excretion rate. At the same time rhr-1, nka, vat, and nhx-3 showed higher mRNA expression levels when compared to N2. Also, in contrast to N2 worms, ∆rhr-2 did not show enhanced ammonia excretion rates when exposed to a low pH env...
The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast ... more The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast majority of its nitrogenous waste as ammonia (25.3±1.2 µmol gFW(-1) day(-1)) and very little urea (0.21±0.004 µmol gFW(-1) day(-1)). Although these roundworms have been used for decades as genetic model systems, very little is known about their strategy to eliminate the toxic waste product ammonia from their bodies into the environment. The current study provides evidence that ammonia is at least partially excreted via the hypodermis. Starvation reduced the ammonia excretion rates by more than half, whereas mRNA expression levels of the Rhesus protein CeRhr-2, V-type H(+)-ATPase (subunit A) and Na(+)/K(+)-ATPase (α-subunit) decreased correspondingly. Moreover, ammonia excretion rates were enhanced in media buffered to pH 5 and decreased at pH 9.5. Inhibitor experiments, combined with enzyme activity measurements and mRNA expression analyses, further suggested that the excretion mechanism...
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