scholarly journals Suppression of the dihydrolipoamide dehydrogenase gene (dld-1) protects against the toxicity of human amyloid beta in C. elegans model of Alzheimer’s disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Metabolism ◽  
Mitochondrial Enzymes ◽  
Aβ Peptide ◽  
Dihydrolipoamide Dehydrogenase ◽  
Gene Suppression ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease ◽  
Enzyme Complexes

AbstractDeclines in energy metabolism and associated mitochondrial enzymes are linked to the progression of Alzheimer’s disease (AD). Dihydrolipoamide dehydrogenase (dld) and two of its enzyme complexes namely, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase are associated with AD and have a significant role in energy metabolism. Interestingly, dld gene variants are genetically linked to late-onset AD; and reduced activity of DLD-containing enzyme complexes has been observed in AD patients. To understand how energy metabolism influences AD progression, we suppressed the dld-1 gene in C. elegans expressing the human Aβ peptide. dld-1 gene suppression improved many aspects of vitality and function directly affected by Aβ pathology in C. elegans. This includes protection against paralysis, improved fecundity and improved egg hatching rates. Suppression of the dld-1 gene restores normal sensitivity to aldicarb, levamisole and serotonin, and improves chemotaxis. Suppression of dld-1 does not decrease levels of the Aβ peptide, but does reduce the formation of toxic Aβ oligomers. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) acts synergistically with Aβ to overcome the protective effect of dld-1 gene suppression. Another metabolic toxin, phosphine, acted additively with Aβ. Our work supports the hypothesis that lowering energy metabolism may protect against Aβ pathogenicity, but that this may increase susceptibility to other metabolic disturbances.

scholarly journals Tau aggregates possibly compromise neuronal health in the C. elegans model of Alzheimer’s disease

2020 ◽  
Vol 1 (6) ◽  
pp. 46-48
Author(s):  
Sanjib Guha ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Intercellular Space ◽  
Senile Plaques ◽  
Aβ Peptide ◽  
Progressive Decline ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common degenerative brain disease in the aged population [1]. By 2050, AD prevalence is expected to increase from 4.7 million (based on 2010 census) to 13.8 million people [2]. It is characterized by the progressive decline of cognition and memory, as well as changes in behavior and personality [1]. Pathological hallmarks of AD include mainly formation of senile plaques consisting of amyloid-beta (Aβ) peptide in the intercellular space and neurofibrillary tangles (NFTs) in the cell bodies, which are primarily composed of abnormally modified tau protein [3].

scholarly journals Dihydrolipoamide dehydrogenase suppression induce human tau phosphorylation by increasing whole body glucose levels in a C. elegans model of Alzheimer’s Disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Metabolism ◽  
Tau Protein ◽  
Tau Phosphorylation ◽  
Whole Body ◽  
Ionophore A23187 ◽  
Dihydrolipoamide Dehydrogenase ◽  
C Elegans ◽  
Glucose Levels

AbstractThe microtubule associated tau protein becomes hyperphosphorylated in Alzheimer’s disease (AD). While hyperphosphorylation promotes neurodegeneration, the cause and consequences of this abnormal modification are poorly understood. As impaired energy metabolism is an important hallmark of AD progression, we tested whether it could trigger phosphorylation of human tau protein in a transgenic C. elegans model of AD. We found that inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) resulted in elevated whole-body glucose levels as well as increased phosphorylation of tau. Hyperglycemia and tau phosphorylation were induced by either epigenetic suppression of the dld-1 gene or by inhibition of the DLD enzyme by the inhibitor, 2-methoxyindole-2-carboxylic acid (MICA). Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical or genetic suppression of DLD, it was unable to reduce tau phosphorylation induced by hyperglycemia. While inhibition of the dld-1 gene or treatment with MICA partially reversed the inhibition of acetylcholine neurotransmission by tau, neither treatment affected tau inhibited mobility. Conclusively, any abnormalities in energy metabolism were found to significantly affect the AD disease pathology.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

Taurine and Camel Milk Modulate Neurobehavioral and Biochemical Changes in Aluminum Chloride-Induced Alzheimer’s Disease in Rats

2021 ◽  
pp. 1-12
Author(s):  
Teslim S. Abdulkadir ◽  
Fatima A. Dawud ◽  
Ahmed Sherif Isa ◽  
Joseph O. Ayo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Superoxide Dismutase ◽  
Aluminum Chloride ◽  
Motor Coordination ◽  
Acetylcholinesterase Activity ◽  
Camel Milk ◽  
Aβ Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Female Wistar Rats

Background: Alzheimer’s disease (AD) is a neurodegenerative disease associated with deficiency in motor coordination, cognitive impairment, and excessive reactive oxygen species production in the brain. Objective: The study evaluated effects of taurine and camel milk (CM) on neurobehavior, amyloid-beta peptide 1–42 (Aβ) expression, acetylcholinesterase, and superoxide dismutase activities in aluminum chloride (AlCl3) model of Alzheimer’s disease in rats. Methods: Thirty-five female Wistar rats were divided into seven groups (n = 5): Normal saline (0.2 mL/kg body weight); AlCl3 (100 mg/kg) (AD); CM (33 mL/kg); Taurine (50 mg/kg); AlCl3 (100 mg/kg) + CM (33 mL/kg); AlCl3 (100 mg/kg) + Taurine (50 mg/kg); and AlCl3 (100 mg/kg) + CM (33 mL/kg) + Taurine (50 mg/kg). The administration lasted for eight weeks via oral gavage. After the eighth week, neurobehavior assessments were performed. Rats were sacrificed, and brain and blood samples collected for analysis. Results: There was a significant (p <  0.0001) increase in the duration of motor endurance in AD + CM rats, compared to AD rats. Duration of forced swimming time was lowest (p <  0.0001) in AlCl3 + Taurine rats, compared to that of AD rats. Concentration of Aβ peptide decreased (p <  0.05) in AD rats, treated with CM and/or combination. In taurine-treated rats, superoxide dismutase activity was significantly (p <  0.05) higher than in AD rats. Treatment with taurine + CM increased (p <  0.05) acetylcholinesterase activity compared to controls. Conclusion: Taurine and CM enhanced cognition and sensorimotor activity by decreasing Aβ peptide concentration and increasing superoxide dismutase and acetylcholinesterase activities in AD rats.

Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease

Nature ◽  
2000 ◽  
Vol 408 (6815) ◽  
pp. 982-985 ◽  
Author(s):  
Dave Morgan ◽  
David M. Diamond ◽  
Paul E. Gottschall ◽  
Kenneth E. Ugen ◽  
Chad Dickey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Memory Loss ◽  
Aβ Peptide ◽  
Peptide Vaccination ◽  
Model Of Alzheimer’S Disease

scholarly journals Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rachel E. Lackie ◽  
Jose Marques-Lopes ◽  
Valeriy G. Ostapchenko ◽  
Sarah Good ◽  
Wing-Yiu Choy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Quality ◽  
Amyloid Β ◽  
Amyloid Burden ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

scholarly journals Erratum: correction: Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease

Nature ◽  
2001 ◽  
Vol 412 (6847) ◽  
pp. 660-660 ◽  
Author(s):  
Dave Morgan ◽  
David M. Diamond ◽  
Paul E. Gottschall ◽  
Kenneth E. Ugen ◽  
Chad Dickey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Memory Loss ◽  
Aβ Peptide ◽  
Peptide Vaccination ◽  
Model Of Alzheimer’S Disease

scholarly journals ROLE OF RADIATION AS EFFECTIVE INTERVENTION IN Aβ INDUCED OXIDATIVE STRESS IN ANIMAL MODEL OF ALZHEIMER’S DISEASE

2019 ◽  
Vol 12 (1) ◽  
pp. 227
Author(s):  
Khan A ◽  
Kamal R ◽  
Dhawan Dk ◽  
Vijayta Dani Chadha
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Antioxidant Defense ◽  
Low Dose ◽  
Effective Intervention ◽  
Aβ Peptide ◽  
Model Of Alzheimer’S Disease ◽  
X Irradiation

Objective: The present study was undertaken to study the therapeutic effects of low dose fractionated cranial X-irradiation on reducing the amyloid-beta (Aβ) induced oxidative stress burden in an animal model of Alzheimer’s disease (AD).Methods: S.D. female rats received an intracerebroventricular injection of Aβ peptide at stereotaxically defined points. Experimental sessions were conducted by randomly dividing animals into four groups, namely sham-operated, Aβ-injected, and Aβ injection followed by cranial X-irradiation and only cranial X-irradiated. Anesthetized animals received 5 μl synthetic Aβ peptide injection with a 10 μl Hamilton microsyringe with the needle kept in place for a period of 2min following injection. Sham-operated group received 5 μl of bidistilled water instead of Aβ peptide. Animals were treated 6 weeks post-surgery with fractionated radiation of 2Gy for 5 days. Neurobehavior studies were undertaken to confirm memory impairment along with biochemical indices involved in the antioxidant defense system.Results: Fractionated cranial X-irradiation proved effective in restoration of activity of enzymes involved in the antioxidant defense system; the lipid peroxidation and catalase levels that showed a significant increase in Aβ-treated group decreased on subsequent X-irradiation. Moreover, the decrease in the superoxide dismutase, glutathione, glutathione-S-transferase, and glutathione reductase levels witnessed an increase post-irradiation, implicating the X-irradiation to be an effective intervention to restore the redox status of the oxidatively stressed brain cells in AD condition.Conclusion: The present study evaluated the therapeutic potential of low dose fractionated cranial X- irradiation by mitigating the amyloid-induced oxidative stress suggesting a novel treatment for AD-associated pathologies.

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