Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation in vitro and in vivo

Schweig, Jonas Elias; Yao, Hailan; Coppola, Kyle; Chen, Jin; Crawford, Fiona; Mullan, Michael; Paris, Daniel

doi:10.1074/jbc.ra119.008033

Cited by 37 publications

(42 citation statements)

References 81 publications

(103 reference statements)

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Section: Discussionsupporting

confidence: 86%

“…Nevertheless, nilvadipine did attenuate total tau levels in both sham and r-mTBI mice suggesting its ability to suppress total tau regardless of injury. Consistent with this, we have previously reported that SYK inhibition at 30 weeks of age (when tau pathology is prevalent) decreased total tau in P301S mice [ 28 ]. Schweig et al demonstrated that inhibition of SYK did not affect expression of total tau but rather increased its degradation via an mTOR-dependent autophagy pathway [ 28 ].…”

Section: Discussionsupporting

confidence: 85%

“…Schweig et al demonstrated that inhibition of SYK did not affect expression of total tau but rather increased its degradation via an mTOR-dependent autophagy pathway [28].…”

Section: Discussionmentioning

confidence: 99%

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Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI

Morin

Mouzon

Ferguson

et al. 2020

acta neuropathol commun

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Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (−)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (−)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 85%

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Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI

Morin

Mouzon

Ferguson

et al. 2020

acta neuropathol commun

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“…The 100 datasets are class-imbalanced (e.g., 31 and 500 positive and negative cases, respectively) and classification using class-imbalanced data is biased in favour of the majority class. Further, in the datasets, the number of positive cases are too small, i.e., there are only 31 positive cases in the datasets.…”

Section: Network Embedding: Deep Autoencoder Based Dimensional Reductmentioning

confidence: 99%

“…They also demonstrated that, in those with overexpression of Tau, SKY activated in microglia and misfolded and hyperphosphorylated tau accumulated in hippocampus and cortex. Furthermore, Schweig et al demonstrated that, by immunoprecipitation and RT-PCR experiments, SYK inhibition induces reduction of Tau in an autophagic manner[31]. They also showed that SYK acts as an upstream target in the mTOR pathway and SYK inhibition induces Tau degradation through decreasing mTOR pathway activation.…”

mentioning

confidence: 99%

Artificial intelligence based computational framework for drug-target prioritization and inference of novel repositionable drugs for Alzheimer’s disease

Tsuji

Hase

Yachie‐Kinoshita

et al. 2020

Preprint

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BackgroundIdentification of novel therapeutic targets is a key for successful drug development. However, the cost to experimentally identify therapeutic targets is huge and only 400 genes are targets for FDA-approved drugs. Therefore, it is inevitable to develop powerful computational tools to identify potential novel therapeutic targets. Because proteins make their functions together with their interacting partners, a protein-protein interaction network (PIN) in human could be a useful resource to build computational tools to investigate potential targets for therapeutic drugs. Network embedding methods, especially deep-learning based methods would be useful tools to extract an informative low-dimensional latent space that contains enough information required to fully represent original high-dimensional non-linear data of PINs.ResultsIn this study, we developed a deep learning based computational framework that extracts low-dimensional latent space embedded in high-dimensional data of the human PIN and uses the features in the latent space (latent features) to infer potential novel targets for therapeutic drugs. We examined the relationships between the latent features and the representative network metrics and found that the network metrics can explain a large number of the latent features, while several latent features do not correlate with all the network metrics. The results indicate that the features are likely to capture information that the representative network metrics can not capture, while the latent features also can capture information obtained from the network metrics. Our computational framework uses the latent features together with state-of-the-art machine learning techniques to infer potential drug target genes. We applied our computational framework to prioritized novel putative target genes for Alzheimer’s disease and successfully identified key genes for potential novel therapeutic targets (e.g., DLG4, EGFR, RAC1, SYK, PTK2B, SOCS1). Furthermore, based on these putative targets, we inferred repositionable candidate-compounds for the disease (e.g., Tamoxifen, Bosutinib, and Dasatinib)DiscussionsOur computational framework could be powerful computational tools to efficiently prioritize new therapeutic targets and drug repositioning. It is pertinent to note here that our computational platform is easily applicable to investigate novel potential targets and repositionable compounds for any diseases, especially for rare diseases.

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Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

Potjewyd

Annor-Gyamfi

Aubé

et al. 2022

A&D Transl Res & Clin Interv

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Introduction A chemogenomic set of small molecules with annotated activities and implicated roles in Alzheimer's disease (AD) called the AD Informer Set was recently developed and made available to the AD research community: https://treatad.org/data-tools/ad-informer-set/. Methods Small subsets of AD Informer Set compounds were selected for AD‐relevant profiling. Nine compounds targeting proteins expressed by six AD‐implicated genes prioritized for study by Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT‐AD) teams were selected for G‐protein coupled receptor (GPCR), amyloid beta (Aβ) and tau, and pharmacokinetic (PK) studies. Four non‐overlapping compounds were analyzed in microglial cytotoxicity and phagocytosis assays. Results The nine compounds targeting CAPN2, EPHX2, MDK, MerTK/FLT3, or SYK proteins were profiled in 46 to 47 primary GPCR binding assays. Human induced pluripotent stem cell (iPSC)‐derived neurons were treated with the same nine compounds and secretion of Aβ peptides (Aβ40 and Aβ42) as well as levels of phosphophorylated tau (p‐tau, Thr231) and total tau (t‐tau) peptides measured at two concentrations and two timepoints. Finally, CD1 mice were dosed intravenously to determine preliminary PK and/or brain‐specific penetrance values for these compounds. As a final cell‐based study, a non‐overlapping subset of four compounds was selected based on single‐concentration screening for analysis of both cytotoxicity and phagocytosis in murine and human microglia cells. Discussion We have demonstrated the utility of the AD Informer Set in the validation of novel AD hypotheses using biochemical, cellular (primary and immortalized), and in vivo studies. The selectivity for their primary targets versus essential GPCRs in the brain was established for our compounds. Statistical changes in tau, p‐tau, Aβ40, and/or Aβ42 and blood–brain barrier penetrance were observed, solidifying the utility of specific compounds for AD. Single‐concentration phagocytosis results were validated as predictive of dose–response findings. These studies established workflows, validated assays, and illuminated next steps for protein targets and compounds.

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Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation in vitro and in vivo

Cited by 37 publications

References 81 publications

Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI

Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI

Artificial intelligence based computational framework for drug-target prioritization and inference of novel repositionable drugs for Alzheimer’s disease

Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

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