Dantrolene, A Treatment for Alzheimer Disease?

Li, Liang; Wei, Huafeng

doi:10.1097/wad.0000000000000076

Cited by 34 publications

(31 citation statements)

References 108 publications

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“…Previous studies on the ADNI dataset have also reported significant genetic interactions for CACNA1C using Positron Emission Tomography (PET) imaging (Koran et al, 2014) and LASSO screening with candidate phenotypes (Yang et al, 2015), which all involve certain ‘ conditioning ’ for the contribution from CACNA1C to be detected. Animal AD models have confirmed several results from human studies (Hopp et al, 2014) and related pathways have been identified as a therapeutic target (Liang and Wei, 2015) for AD. Interestingly, a recent multi-site large-scale voxel level functional connectivity study, which included 939 subjects, has revealed that functional connectivity patterns in the orbitofrontal cortex region are significantly altered in depression patients (Cheng et al, 2016).…”

Section: Discussionsupporting

confidence: 53%

Generalized reduced rank latent factor regression for high dimensional tensor fields, and neuroimaging-genetic applications

et al. 2017

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We propose a generalized reduced rank latent factor regression model (GRRLF) for the analysis of tensor field responses and high dimensional covariates. The model is motivated by the need from imaging-genetic studies to identify genetic variants that are associated with brain imaging phenotypes, often in the form of high dimensional tensor fields. GRRLF identifies from the structure in the data the effective dimensionality of the data, and then jointly performs dimension reduction of the covariates, dynamic identification of latent factors, and nonparametric estimation of both covariate and latent response fields. After accounting for the latent and covariate effects, GRLLF performs a nonparametric test on the remaining factor of interest. GRRLF provides a better factorization of the signals compared with common solutions, and is less susceptible to * Corresponding author at: Centre for Computational Systems Biology and School of Mathematical Sciences, Fudan University, Shanghai, PR China. jianfeng64@gmail.com (J. Feng). 1 Data used in preparation of this article were obtained from the Alzheimers Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdfThe authors report no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript overfitting because it exploits the effective dimensionality. The generality and the flexibility of GRRLF also allow various statistical models to be handled in a unified framework and solutions can be efficiently computed. Within the field of neuroimaging, it improves the sensitivity for weak signals and is a promising alternative to existing approaches. The operation of the framework is demonstrated with both synthetic datasets and a real-world neuroimaging example in which the effects of a set of genes on the structure of the brain at the voxel level were measured, and the results compared favorably with those from existing approaches.

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Section: Discussionsupporting

confidence: 53%

Generalized reduced rank latent factor regression for high dimensional tensor fields, and neuroimaging-genetic applications

et al. 2017

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“…Moreover, treatment of FAD transgenic mice with dantrolene has been found by several laboratories to be effective in reversing a range of AD features, including aberrant ER Ca 2+ signaling, disrupted hippocampal synaptic plasticity mechanisms, behavioral deficits, and Aβ plaque deposition [84]. In our laboratory, we found that a 4-week treatment with a brain penetrant nanocrystal formulation of dantrolene normalized the elevated hippocampal RyR2 expression and aberrantly high somatic and dendritic RyR Ca 2+ responses in pyramidal neurons from 3xTg and APP/PS1 FAD mice, restored normal short-term and long-term synaptic plasticity mechanisms in 3xTg mice, and reduced the levels of soluble and insoluble Aβ in cortex and hippocampus of APP/PS1 mice [22].…”

Section: Opportunities For Therapeuticsmentioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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“…6D) is structurally very similar to LPA; however, two of its hydroxyl groups are esterified with fatty acid chains, and the third hydroxyl group is esterified with phosphoric acid. It is both a modulator of membrane shape and a second messenger [see (Ammar et al, 2014) for review]. PA displays a variety of functions, being involved in the intracellular transport of target proteins via PA vesicles (Henkels et al, 2016) and playing a major role in the development of the nervous system (Ammar et al, 2014).…”

Section: Signal Transductionmentioning

confidence: 99%

“…It is both a modulator of membrane shape and a second messenger [see (Ammar et al, 2014) for review]. PA displays a variety of functions, being involved in the intracellular transport of target proteins via PA vesicles (Henkels et al, 2016) and playing a major role in the development of the nervous system (Ammar et al, 2014). Similarly, cyclic phosphatidic acid (cPA), a naturally occurring analog of LPA (Fig.…”

Section: Signal Transductionmentioning

confidence: 99%

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Biologic activity of cyclic and caged phosphates: a review

Lorke

Stegmeier-Petroianu

Petroianu

2016

J of Applied Toxicology

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The recognition in the early 1960s by Morifusa Eto that tri-o-cresyl phosphate (TOCP) is hydroxylated by the cytochrome P450 system to an intermediate that spontaneously cyclizes to a neurotoxic phosphate (saligenin phosphate ester) ignited the interest in this group of compounds. Only the ortho isomer can cyclize and clinically cause Organo Phosphate Induced Delayed Neurotoxicity (OPIDN); the meta and para isomers of tri-cresyl phosphate are not neuropathic because they are unable to form stable cyclic saligenin phosphate esters. This review identifies the diverse biological effects associated with various cyclic and caged phosphates and phosphonates and their possible use. Cyclic compounds that inhibit acetylcholine esterase (AChE), such as salithion, can be employed as pesticides. Others are neurotoxic, most probably because of inhibition of neuropathy target esterase (NTE). Cyclic phosphates that inhibit lipases, the cyclipostins, possibly represent promising therapeutic avenues for the treatment of type 2 diabetes mellitus and/or microbial infections; those compounds inhibiting β-lactamase may prevent bacterial resistance against β-lactam antibiotics. Naturally occurring cyclic phosphates, such as cyclic AMP, cyclic phosphatidic acid and the ryanodine receptor modulator cyclic adenosine diphosphate ribose, play an important physiological role in signal transduction. Moreover, some cyclic phosphates are GABA-antagonists, while others are an essential component of Molybdenum-containing enzymes. Some cyclic phosphates (cyclophosphamide, ifosfamide) are clinically used in tumor therapy, while the coupling of therapeutic agents with other cyclic phosphates (HepDirect® Technology) allows drugs to be targeted to specific organs. Possible clinical applications of these compounds are considered. Copyright © 2016 John Wiley & Sons, Ltd.

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Dantrolene, A Treatment for Alzheimer Disease?

Cited by 34 publications

References 108 publications

Generalized reduced rank latent factor regression for high dimensional tensor fields, and neuroimaging-genetic applications

Generalized reduced rank latent factor regression for high dimensional tensor fields, and neuroimaging-genetic applications

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Biologic activity of cyclic and caged phosphates: a review

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