Metformin Attenuates Aβ Pathology Mediated Through Levamisole Sensitive Nicotinic Acetylcholine Receptors in a C. elegans Model of Alzheimer’s Disease

Ahmad, Waqar; Ebert, Paul R.

doi:10.1007/s12035-016-0085-y

Cited by 51 publications

(19 citation statements)

References 86 publications

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“…These remarkable results point out the possible mode of action of CLE metabolites apart from conventional criteria, such as interactions with Aβ-related proteins like the peroxisome proliferator-activated receptor gamma (PPARγ) and pro-apoptotic proteins—respectively known to be upregulated and downregulated by natural products such as epigallocatechin gallate (EGCG) in green tea [29]. Further, CLE may instead be interacting with known proteins affecting Aβ deposition in C. elegans , such as DAF-2 and FOXO [46,47], all of which warrant further investigation on the possible mechanisms on CLE metabolites.…”

Section: Discussionmentioning

confidence: 99%

Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

Manalo

Silvestre²,

Barbosa³

et al. 2017

Biomedicines

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Virgin coconut oil (VCO) has been the subject of several studies which have aimed to alleviate Alzheimer’s disease (AD) pathology, focusing on in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Here, we studied an underutilized and lesser-valued part of the coconut tree, specifically the leaves, using in vitro and in vivo approaches. Coconut leaf extract (CLE) was screened for antioxidant and AChE inhibitory properties in vitro and therapeutic effects in two strains of transgenic Caenorhabditis elegans expressing amyloid-β1–42 (Aβ1-42) in muscle cells. CLE demonstrated free radical scavenging activity with an EC50 that is 79-fold less compared to ascorbic acid, and an AChE inhibitory activity that is 131-fold less compared to Rivastigmine. Surprisingly, in spite of its low antioxidant activity and AChE inhibition, CLE reduced Aβ deposits by 30.31% in CL2006 in a dose-independent manner, and reduced the percentage of paralyzed nematodes at the lowest concentration of CLE (159.38 μg/mL), compared to dH2O/vehicle (control). Phytochemical analysis detected glycosides, anthocyanins, and hydrolyzable tannins in CLE, some of which are known to be anti-amyloidogenic. Taken together, these findings suggest that CLE metabolites alternatively decrease AB1–42 aggregation and paralysis prevalence independently of free radical scavenging and AChE inhibition, and this warrants further investigation on the bioactive compounds of CLE.

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Section: Discussionmentioning

confidence: 99%

Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

Manalo

Silvestre²,

Barbosa³

et al. 2017

Biomedicines

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“…As MICA restored cholinergic neurotransmission in worms that express Aβ in muscle cells, we reasoned that MICA might also reduce Aβ-mediated toxicity in worms that express Aβ in neurons. In our previous study, we found that metformin, a well-known hypoglycemic agent, improved chemotaxis and restored normal serotonin-sensitivity in worms that express Aβ in neurons [2]. Similar findings were observed for MICA in this study suggesting that the two compounds have a similar mode of action.…”

Section: Discussionsupporting

confidence: 88%

“…As we found negative effects of glucose enrichment on AD progression, we hypothesized that the antidiabetic drugs' metformin and AICAR could also be beneficial in AD. Both metformin and AICAR reduced Aβ -mediated toxicity in worms suggesting that anti-diabetic drugs might be helpful to slow/ overcome AD pathogenesis [608].…”

Section: Chapter # Viii: General Discussionmentioning

confidence: 99%

Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

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“…For instance, we have previously shown that antioxidant treatment, using the mitochondrial-targeted antioxidant MitoQ, was able to ameliorate depletion of the mitochondrial lipid cardiolipin and improved the healthspan of another strain of transgenic AD nematodes with muscular expression of Aβ (CL2006) 35 . Treatment using an antidiabetic drug, Metformin, has also recently been shown to delay Aβ-related paralysis, and improve neuronal transmission, in two transgenic AD strains, one with inducible muscular (CL4176) and one with neuronal Aβ expression (CL2355) 36 . However, the mechanisms underlying the beneficial AD effects of such metabolism-related drugs are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta

Teo

Ravi

Barardo

et al. 2019

Preprint

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26Alzheimer's disease (AD) is the most common neurodegenerative disease affecting 27 the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in 28 the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced 29 mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by 30 expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a 31 deeper analysis of these metabolic changes associated with A-induced mitochondrial 32 dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and 33 computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle 34 metabolism following even low-level Aβ expression. In particular, GRU102 show 35 reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate 36 dehydrogenase. These defects are associated with elevation of protein carbonyl 37 content specifically in mitochondria. Importantly, metabolic failure occurs before any 38 significant increase in global protein aggregate is detectable. Treatment with an anti-39 diabetes drug, Metformin, reverses A-induced metabolic defects, reduces protein 40 aggregation and normalizes the lifespan of GRU102. Our results point to metabolic 41 dysfunction as an early and causative event in AD pathology and a promising target 42 for intervention. 43 44 45 46 47 48 49 50 51 Introduction 52Alzheimer's disease (AD) is a debilitating neurodegenerative disease, that is clinically 53 characterized by the formation of amyloid-beta (A) plaques and aggregates of 54 hyperphosphorylated tau protein in the brain 1 . Even though AD is primarily a 55 neuronal disorder, perturbations in mitochondrial functions including energy 56 metabolism have consistently been observed not only in the brain 2-4 but also in non-57 neuronal cells derived from AD subjects, including in fibroblasts and platelets [5][6][7][8][9][10] . 58These findings form part of an emerging story that there is an important metabolic 59 component to the etiology of AD 11 , and that these metabolic defects may precede A 60 aggregate formation 12,13 . The metabolism-related hypothesis of AD therefore posits 61 that AD is, in part, mediated by impairments to the brain's insulin response, which 62 promotes oxidative stress and inflammation, similar to that seen in diabetes 11,14 . 63Intranasal insulin treatment has been shown to ameliorate AD pathology in a 64 transgenic rat model and to improve mild cognitive impairment (MCI) in patients [15][16][17][18] . 65 66Several animal studies have confirmed that oxidative stress, mitochondrial 67 dysfunction and metabolic alterations are early events in the pathophysiological 68 progression of AD. Energy deficits, reduction in mitochondrial membrane potential, 69 abnormal mitochondrial gene expression and increased oxidative stress have been 70 observed early in transgenic AD mice (2-3 months of age) well before the appearance 71 of A plaques 19,20 . The A-induced oxidative stress hypothesis further posits that A, 72 predomi...

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Metformin Attenuates Aβ Pathology Mediated Through Levamisole Sensitive Nicotinic Acetylcholine Receptors in a C. elegans Model of Alzheimer’s Disease

Cited by 51 publications

References 86 publications

Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

Metabolic study of Alzheimer’s disease using mutant C. elegans

Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta

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