BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer’s disease models

Nishioka, Hisae; Tooi, Norie; Isobe, Takehisa; Nakatsuji, Norio; Aiba, Keisuke

doi:10.1038/srep33427

Cited by 24 publications

(9 citation statements)

References 48 publications

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“…SV2B KO mice subjected to toxic species of amyloid-β protein are protected from both memory decline and decrease in CHAT activity in the hippocampus [10], opening up the possibility that SV2B is needed to regulate CHAT. Furthermore, reduced SV2B expression has also been found in other neurodegenerative diseases connected to acetylcholine [56][57][58]. The co-regulation between SV2B and CHAT in the neuroblastoma cell lines used here indicates that interconnectivity exists between SV2B and CHAT even outside of disease models where SV2B is missing, or due to failure in cholinergic neurons.…”

Section: Discussionsupporting

confidence: 56%

Differentiation of two human neuroblastoma cell lines alters SV2 expression patterns

et al. 2021

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Background The synaptic vesicle glycoprotein 2 (SV2) family is essential to the synaptic machinery involved in neurotransmission and vesicle recycling. The isoforms SV2A, SV2B and SV2C are implicated in neurological diseases such as epilepsy, Alzheimer’s and Parkinson’s disease. Suitable cell systems for studying regulation of these proteins are essential. Here we present gene expression data of SV2A, SV2B and SV2C in two human neuroblastoma cell lines after differentiation. Methods Human neuroblastoma cell lines SiMa and IMR-32 were treated for seven days with growth supplements (B-27 and N-2), all-trans-retinoic acid (ATRA) or vasoactive intestinal peptide (VIP) and gene expression levels of SV2 and neuronal targets were analyzed. Results The two cell lines reacted differently to the treatments, and only one of the three SV2 isoforms was affected at a time. SV2B and choline O-acetyltransferase (CHAT) expression was changed in concert after growth supplement treatment, decreasing in SiMa cells while increasing in IMR-32. ATRA treatment resulted in no detected changes in SV2 expression in either cell line while VIP increased both SV2C and dopamine transporter (DAT) in IMR-32 cells. Conclusion The synergistic expression patterns between SV2B and CHAT as well as between SV2C and DAT mirror the connectivity between these targets found in disease models and knock-out animals, although here no genetic alteration was made. These cell lines and differentiation treatments could possibly be used to study SV2 regulation and function.

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Section: Discussionsupporting

confidence: 56%

Differentiation of two human neuroblastoma cell lines alters SV2 expression patterns

et al. 2021

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“…Tyrosine kinase inhibitors have an anti-inflammatory effect through modulation of various markers of neuroinflammation in animal models [ 40 , 41 ]. Nilotinib was associated with rescued synaptic dysfunction [ 46 ]. Both nilotinib and bosutinib were found to prevent cell death due to trans-activating response of DNA/RNA-binding protein (TDP)-43 pathology, but only nilotinib reversed mitochondrial impairment [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

O’Brien

Chouliaras²,

Sultana³

et al. 2022

Alz Res Therapy

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Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson’s disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia.

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“…In a mouse model of AD, nilotinib decreases Aβ-plaque-induced increases in proinflammatory cytokine levels in the hippocampus, and in patients with AD or PD, nilotinib improves learning/memory behavior [ 12 – 14 , 23 ]. Nilotinib significantly restores synaptic function in human cellular AD models by increasing the levels of the synaptic proteins Rab3A and SV2B [ 55 ]. Six months of treatment with nilotinib (150 mg and 300 mg) improves cognition in patients with Parkinson’s disease compared to baseline [ 13 ], whereas Cludiani et al reported that leukemia patients treated with nilotinib experience memory dysfunction 4–6 months after cessation [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

Kim

Lee

Park

et al. 2022

J Neuroinflammation

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Background In chronic myelogenous leukemia, reciprocal translocation between chromosome 9 and chromosome 22 generates a chimeric protein, Bcr-Abl, that leads to hyperactivity of tyrosine kinase-linked signaling transduction. The therapeutic agent nilotinib inhibits Bcr-Abl/DDR1 and can cross the blood–brain barrier, but its potential impact on neuroinflammatory responses and cognitive function has not been studied in detail. Methods The effects of nilotinib in vitro and in vivo were assessed by a combination of RT-PCR, real-time PCR, western blotting, ELISA, immunostaining, and/or subcellular fractionation. In the in vitro experiments, the effects of 200 ng/mL LPS or PBS on BV2 microglial cells, primary microglia or primary astrocytes pre- or post-treated with 5 µM nilotinib or vehicle were evaluated. The in vivo experiments involved wild-type mice administered a 7-day course of daily injections with 20 mg/kg nilotinib (i.p.) or vehicle before injection with 10 mg/kg LPS (i.p.) or PBS. Results In BV2 microglial cells, pre- and post-treatment with nilotinib altered LPS-induced proinflammatory/anti-inflammatory cytokine mRNA levels by suppressing AKT/P38/SOD2 signaling. Nilotinib treatment also significantly downregulated LPS-stimulated proinflammatory cytokine levels in primary microglia and primary astrocytes by altering P38/STAT3 signaling. Experiments in wild-type mice showed that nilotinib administration affected LPS-mediated microglial/astroglial activation in a brain region-specific manner in vivo. In addition, nilotinib significantly reduced proinflammatory cytokine IL-1β, IL-6 and COX-2 levels and P38/STAT3 signaling in the brain in LPS-treated wild-type mice. Importantly, nilotinib treatment rescued LPS-mediated spatial working memory impairment and cortical dendritic spine number in wild-type mice. Conclusions Our results indicate that nilotinib can modulate neuroinflammatory responses and cognitive function in LPS-stimulated wild-type mice.

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BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer’s disease models

Cited by 24 publications

References 48 publications

Differentiation of two human neuroblastoma cell lines alters SV2 expression patterns

Differentiation of two human neuroblastoma cell lines alters SV2 expression patterns

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

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