AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice

Khandelwal, Mayuri; Manglani, Kapil; Upadhyay, Prabhat; Azad, Mohammad Abul Kalam; Gupta, Sarika

doi:10.1016/j.nbd.2022.105876

Cited by 25 publications

(16 citation statements)

References 74 publications

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“… 55 Microvascular function can affect collateral circulation in macrovessels 56 , 57 and increase the risk of stroke 58 as well as a poor prognosis. 59 – 61 Neurons injury, 62 Alzheimer’s like pathologies, 63 and abnormal activity of neurotransmitter receptors 64 are also closely associated with cerebrovascular lesions, and jointly cause brain function impairment in patients.…”

Section: Introductionmentioning

confidence: 99%

“…The accumulation of AGEs also affects various cellular constituents of the BBB, resulting in increased BBB permeability and cognitive impairment. 97 – 99 Vascular endothelial dysfunction further promotes the production of inflammatory mediators that disrupt the BBB, 59 , 63 , 64 , 100 which exposes the brain parenchyma to potentially neurotoxic proteins. 101 Classical inflammatory mediators such as IL-1β, IL-6, IL-10, TNF-α, vascular cell adhesion protein-1 (VCAM-1), and matrix metalloproteinases (MMP)-2 and -9 suggest vascular neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

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Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

Liu

et al. 2023

Sig Transduct Target Ther

110

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Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease (DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment, basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts, mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

Liu

et al. 2023

Sig Transduct Target Ther

110

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“…Alzheimer's disease is a devastating neurodegenerative disease characterized by intracellular neurofibrillary tau tangles and extracellular Aβ plaque accumulation, which is recognized as the largest unmet health problem leading to brain shrinkage. 20 The available drugs for AD, primarily including acetylcholinesterase inhibitors and memantine, the NMDA receptor antagonist, are only temporarily effective in ameliorating cognitive decline but unable to halt or reverse disease progression. 21 Therefore, new drugs that could retard or slow AD progression are pressingly needed.…”

Section: Discussionmentioning

confidence: 99%

“…The interactions of quinidine sulfate(10,20,40, 80, 160, and 320 μM) and donepezil hydrochloride(20,40, 80, 160, 320, and 640 μM) with NMDA-2A by injection amount-dependent analysis. The chromatograms of quinidine sulfate (A) and donepezil hydrochloride (D) on NMDA-2A column; the regression curves of quinidine sulfate (B) and donepezil hydrochloride (E) by plotting kn I /(1 + k) versus kV m ; the structure of quinidine sulfate (C) and donepezil hydrochloride (F).…”

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confidence: 99%

N‐methyl‐D‐aspartic acid receptor 2A functionalized stationary phase: A reliable method for pursuing potential ligands against Alzheimer's disease from natural products

et al. 2023

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Aims: N-methyl-D-aspartic acid (NMDA) receptors play subunit-specific role in central neuronal development. However, insights into the pharmacological modulation of NMDA receptors were mainly lack of subunit and synaptic selectivity. The purpose of the present study was to develop a novel strategy to rapidly recognize NMDA subunit 2A (NMDA-2A) ligands from natural products and provide subunit-selective drug candidates for Alzheimer's disease (AD). Methods:The recombinant NMDA-2A containing a tag of epidermal growth factor receptor (EGFR) was expressed in Escherichia coli cells and immobilized on ibrutinibmodified microspheres based on the specific reaction between EGFR and its inhibitor ibrutinib. A novel affinity stationary phase was synthesized to screen NMDA-2A ligands from Gardenia jasminoides Ellis. Results:The immobilized receptor column exhibited excellent receptor selectivity and ligand-binding activity. Crocetin was screened by using this method. In a cellular model of AD, the protein level of NMDA-2A was significantly decreased compared with the control group, while treatment with crocetin significantly increased NMDA-2A level in a concentration-dependent manner, confirming that crocetin could bind to NMDA-2A in vitro. Conclusion:In the present study, we developed a reliable method for the rapid identification of NMDA-2A ligands from natural products, which may be used as a platform for new drug discovery to generate high-quality drug candidates.

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“…AdipoRon, an orally active adiponectin receptor agonist, binds with high affinity to the adiponectin receptors AdipoR1 and AdipoR2, which acts via 5’ adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPARα) pathways, respectively [ 10 ]. Importantly, AdipoRon acts in a manner consistent with the activity of adiponectin in a number of physiological systems [ 11 , 12 , 13 , 14 , 15 , 16 ]. Recently, Crosson and colleagues found that adiponectin receptors are highly expressed in mice taste buds [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Adiponectin Enhances Fatty Acid Signaling in Human Taste Cells by Increasing Surface Expression of CD36

Lin

Liu

Rudeski-Rohr

et al. 2023

IJMS

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Adiponectin, a key metabolic hormone, is secreted into the circulation by fat cells where it enhances insulin sensitivity and stimulates glucose and fatty acid metabolism. Adiponectin receptors are highly expressed in the taste system; however, their effects and mechanisms of action in the modulation of gustatory function remain unclear. We utilized an immortalized human fungiform taste cell line (HuFF) to investigate the effect of AdipoRon, an adiponectin receptor agonist, on fatty acid-induced calcium responses. We showed that the fat taste receptors (CD36 and GPR120) and taste signaling molecules (Gα-gust, PLCβ2, and TRPM5) were expressed in HuFF cells. Calcium imaging studies showed that linoleic acid induced a dose-dependent calcium response in HuFF cells, and it was significantly reduced by the antagonists of CD36, GPR120, PLCβ2, and TRPM5. AdipoRon administration enhanced HuFF cell responses to fatty acids but not to a mixture of sweet, bitter, and umami tastants. This enhancement was inhibited by an irreversible CD36 antagonist and by an AMPK inhibitor but was not affected by a GPR120 antagonist. AdipoRon increased the phosphorylation of AMPK and the translocation of CD36 to the cell surface, which was eliminated by blocking AMPK. These results indicate that AdipoRon acts to increase cell surface CD36 in HuFF cells to selectively enhance their responses to fatty acids. This, in turn, is consistent with the ability of adiponectin receptor activity to alter taste cues associated with dietary fat intake.

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AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice

Cited by 25 publications

References 74 publications

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

N‐methyl‐D‐aspartic acid receptor 2A functionalized stationary phase: A reliable method for pursuing potential ligands against Alzheimer's disease from natural products

Adiponectin Enhances Fatty Acid Signaling in Human Taste Cells by Increasing Surface Expression of CD36

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