An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

Sheline, Yvette I.; West, Tim; Yarasheski, Kevin E.; Swarm, Robert A.; Jasielec, Mateusz S.; Fisher, Jonathan R.; Ficker, Whitney D.; Yan, Ping; Xiong, Chengjie; Frederiksen, Christine; Grzelak, Monica; Chott, Robert; Bateman, Randall J.; Morris, John C.; Mintun, Mark A.; J, Lee; Cirrito, John R.

doi:10.1126/scitranslmed.3008169

Cited by 175 publications

(178 citation statements)

References 42 publications

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“…The Aβ-lowering activity was also accessed directly in human cerebrospinal fluid (CSF) using stable isotope labeling kinetics. CSF sampling during acute dosing of citalopram, demonstrated decreased Aβ in the CSF of the citalopram-treated group [82]. These studies suggest that citalopram and potentially other SSRIs are promising candidate drugs for repositioning.…”

Section: Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 74%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Section: Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 74%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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“…Considering that chronic treatments with RS67333 have already shown their ability to slow down AD pathology and prevent cognitive deficits in mice (36), donecopride opens the door to a previously unidentified class of compounds that could take advantage of the well-known properties of AChE inhibitors, and it could also enhance the serotonergic transmission that seems to be more and more relevant for a cure for AD (40). Undeniably, serotonin signaling is associated with a lowering of Aβ levels in either soluble form or deposits, a decrease that has a positive outcome on cognitive performance in mice and may prevent deleterious amyloid accumulation in AD (40)(41)(42). However, activation of 5-HTR (5-HT 2A , 5-HT 2C , and 5-HT 4 ) has been shown to also induce an increase in soluble form of APPα (34,36,43).…”

Section: Discussionmentioning

confidence: 99%

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Lecoutey

Hédou

Freret

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

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RS67333 is a partial serotonin subtype 4 receptor (5-HT 4 R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitargetdirected ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT 4 R partial agonist (K i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC 50 = 16 nM) that further promotes sAPPα release (EC 50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

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“…The most remarkable advantage of CRANAD-3, compared with other NIRF imaging probes for Aβs, is its ability to detect both soluble and insoluble Aβs, making CRANAD-3 suitable for monitoring the rapid Aβ-lowering effect of BACE-1 inhibitors and other fast-acting drug candidates [i.e., bexarotene (63,(65)(66)(67)(68)(69) and citalopram (70)]. This ability is very important, because our imaging method would enable a quick evaluation of the efficacy of some categories of drug candidates, such as BACE-1 inhibitors, gamma-secretase inhibitors/modulators, and others (62,71).…”

Section: Discussionmentioning

confidence: 99%

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Zhang

Tian

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

199

180

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Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin

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An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

Cited by 175 publications

References 42 publications

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

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