Pharmacological Study on Alzheimer’s Drugs Targeting Calcium/Calmodulin-Dependent Protein Kinase II

Moriguchi, Shigeki

doi:10.1254/jphs.11r06cp

Cited by 14 publications

(6 citation statements)

References 29 publications

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“…Clinically, the lead compounds Nefiracetam and PHA 543613, both of which are orally administered, have invaluable mechanisms of action to treat these deficiencies. Nefiracetam is a cholinergic, GABAergic, and glutamatergic agonist developed to enhance cognitive functioning (Malykh & Sadaie, 2010; Moriguchi, 2011), and PHA 543613 is an α7‐nAChR agonist with proven neuroprotective effects in a neurodevelopmental disease model (Foucault‐Fruchard et al , 2018). Cholinergic modulatory effects within the nervous system are many because nAChRs are widely dispersed across the neuronal and synaptic architecture, and acetylcholine additionally affects the release of other neurotransmitters (Picciotto et al , 2012).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological reversal of synaptic and network pathology in human MECP2 ‐KO neurons and cortical organoids

et al. 2020

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Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.

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Section: Discussionmentioning

confidence: 99%

Pharmacological reversal of synaptic and network pathology in human MECP2 ‐KO neurons and cortical organoids

et al. 2020

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“…There are also other strategies such as kinase inhibition [71], microtubule stabilization [72], vitamin supplementation [73], aggregate disintegration [74], among others, which have been tested in preclinical settings. Application of metal chelators such as clioquinol and PBT2 in arresting A␤ pathology also showed promising results in animal models [75].…”

Section: Treatment For Ad: Focus Beyond Neurotransmittersmentioning

confidence: 99%

Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer’s Disease: What are the Roadblocks and How Can They Be Overcome?1

Banik

Brown

Bamburg

et al. 2015

JAD

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Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

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“…CAMK2N1 is, itself, a potent inhibitor of calcium/calmodulin-dependent protein kinase II (CAMK2), which is a mediator of learning and memory [95]. CAMK2 is currently a target of several anti-AD drugs under investigation [96]. …”

Section: Discussionmentioning

confidence: 99%

PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer’s amyloid-β precursor protein via a tissue-specific proximal regulatory element (PRE)

et al. 2013

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BackgroundAlzheimer’s disease (AD) is intimately tied to amyloid-β (Aβ) peptide. Extraneuronal brain plaques consisting primarily of Aβ aggregates are a hallmark of AD. Intraneuronal Aβ subunits are strongly implicated in disease progression. Protein sequence mutations of the Aβ precursor protein (APP) account for a small proportion of AD cases, suggesting that regulation of the associated gene (APP) may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or “proximal regulatory element” (PRE), at −76/−47, from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay (EMSA) and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones.ResultsEMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 (AP2), nm23 nucleoside diphosphate kinase/metastatic inhibitory protein (PuF), and specificity protein 1 (SP1). These sites crossed a known single nucleotide polymorphism (SNP). EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis.ConclusionsWe propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging.

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Pharmacological Study on Alzheimer’s Drugs Targeting Calcium/Calmodulin-Dependent Protein Kinase II

Cited by 14 publications

References 29 publications

Pharmacological reversal of synaptic and network pathology in human MECP2 ‐KO neurons and cortical organoids

Pharmacological reversal of synaptic and network pathology in human MECP2 ‐KO neurons and cortical organoids

Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer’s Disease: What are the Roadblocks and How Can They Be Overcome?1

PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer’s amyloid-β precursor protein via a tissue-specific proximal regulatory element (PRE)

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