Circular Dichroism Spectroscopy Identifies the β-Adrenoceptor Agonist Salbutamol As a Direct Inhibitor of Tau Filament Formation <i>in Vitro</i>

Townsend, David; Mala, Barbora; Hughes, Eleri; Hussain, Rohanah; Siligardi, Giuliano; Fullwood, Nigel J.; Middleton, David A.

doi:10.1021/acschemneuro.0c00154

Cited by 18 publications

(14 citation statements)

References 80 publications

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“…Salbutamol is a frequently used, relatively cheap, and well established selective β2AR agonist available on the Dutch market [ 25 ]. The in vitro study Townsend et al [ 5 ]. reported that salbutamol is able to decrease the rate and yield of filament formation and also that it could inhibit tau’s structural change into aggregates [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…AD is a progressive and irreversible brain disorder with loss of behavioral abilities and cognitive functioning among which reasoning, remembering, perception, language comprehension, and thinking [ 4 ]. Pathological hallmarks of AD are the deposition of tau and amyloid-β (Aβ) in the brain which on the long run can cause neurodegeneration due to the formation of insoluble neurofibrillary tangles and amyloid fibrils (Aβ plaques) [ 5 ]. AD is also characterized by chronic inflammation [ 6, 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer’s Disease: A Retrospective Inception Cohort Study

Hutten

Bos

Vos

2022

JAD

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Background: Animal studies suggested that β2-Adrenergic receptors (β2AR) may be a potential target for the treatment of Alzheimer’s disease (AD). Objective: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the β2AR and the risk of starting treatment for AD in older adults. Methods: A retrospective inception cohort study was conducted among older adults who initiated either non-selective βAR antagonists or selective β2AR agonists using the University Groningen IADB.nl prescription database (study period 1994–2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). Results: The risk of developing AD was elevated among patients exposed to non-selective βAR antagonists (A: aHR 3.303, 95% CI 1.230–8.869, B: aHR 1.569, 95% CI 0.560–4.394) and reduced among patients exposed to selective β2AR agonists (A: aHR 0.049, 95% CI 0.003–0.795, B: aHR 0.834, 95% CI 0.075–9.273) compared to reference patients. Conclusion: These findings suggest that exposure to non-selective βAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective β2AR agonists.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer’s Disease: A Retrospective Inception Cohort Study

Hutten

Bos

Vos

2022

JAD

View full text Add to dashboard Cite

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“…We observed that the albuterol was associated with a consistent 22% reduced risk of AD (HR 0.78, 95% CI 0.74-0.83) in OneFlorida and a 22% reduced risk of AD (HR 0.78, 95% CI 0.76-0.80) in MarketScan. Previous literature generated AD signals from in-vivo screening 28 or rats models 29 (See Supplementary Table 9 for review details). To the best of our knowledge, our work showed the first RWD signal of albuterol for AD.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Clinical Trial Emulation with Real World Data and Machine Learning: A Case Study of Drug Repurposing for Alzheimer’s Disease

Zang

Zhang

et al. 2022

Preprint

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Clinical trial emulation, which is the process of mimicking targeted randomized controlled trials (RCT) with real world data (RWD), has attracted growing attentions and interests in recent years from pharmaceutical industry. Different from RCTs which have stringent eligibility criteria for recruiting participants, RWD are more representative of real world patients whom the drugs will be prescribed to. One technical challenge for trial emulation is how to conduct effective confounding control with complex RWD so that the treatment effects can be objectively derived. Recently many approaches, including deep learning algorithms, have been proposed for this goal, but there is still no systematic evaluation and practical guidance on them. In this paper, we emulate $430,000$ trials from two large-scale RWD warehouses, covering both electronic health records (EHR) and general claims, over 170 million patients spanning more than 10 years, aiming to identify new indications of approved drugs for Alzheimer's disease (AD). We have investigated the behaviors of multiple different approaches including logistic regression and deep learning models, and propose a new model selection strategy that can significantly improve the performance of confounding balance of the participants in different arms of emulated trials. We demonstrate that regularized logistic regression based propensity score (PS) model outperforms deep learning based PS model and others, which contradicts with our intuitions to certain extent. Finally, we identified 8 drugs whose original indications are not AD (pantoprazole, gabapentin, acetaminophen, atorvastatin, albuterol, fluticasone, amoxicillin and omeprazole), hold great potential of being beneficial to AD patients.

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“…More recently, 1280 approved small molecule approved drugs were screened for TH PC potential and one of the hits was levalbuterol, the active molecule in salbutamol/albuterol [157]. This drug is a bronchodilator widely administered for chronic obstructive lung disease and asthma and has been linked to reduced risk and delayed progression of PD and other neuropsychiatric and neurodegenerative disorders [158][159][160][161][162]. Of interest, salbutamol is also suggested to improve the response to L-DOPA therapy in PD by enhancing L-DOPA transport across the BBB [163][164][165].…”

Section: Pharmacological Chaperonesmentioning

confidence: 99%

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

Nygaard

Szigetvari

Grindheim

et al. 2021

JPM

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Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.

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Circular Dichroism Spectroscopy Identifies the β-Adrenoceptor Agonist Salbutamol As a Direct Inhibitor of Tau Filament Formation in Vitro

Abstract: Circular dichroism spectroscopy identifies the β-adrenoceptor agonist salbutamol as a direct inhibitor of tau filament formation in vitro.

Cited by 18 publications

References 80 publications

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer’s Disease: A Retrospective Inception Cohort Study

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer’s Disease: A Retrospective Inception Cohort Study

High-Throughput Clinical Trial Emulation with Real World Data and Machine Learning: A Case Study of Drug Repurposing for Alzheimer’s Disease

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

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