Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

Zhang, Xuemei; Hernández, Israel; Rei, Damien; Mair, Waltraud; Laha, Joydev K.; Cornwell, Madison E.; Cuny, Gregory D.; Tsai, Li‐Huei; Steen, Judith A.; Kosik, Kenneth S.

doi:10.1074/jbc.m112.436402

Cited by 42 publications

(22 citation statements)

References 40 publications

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“…Oral treatment of the 3xTg-AD model with the GSK3β inhibitor MMBO led to decreased tau phosphorylation in AD, as well as in normal control mice [113]. Treatment of 3xTg-AD mice by intraperitoneal (IP) administration with a dual GSK3β-CDL5/p25 inhibitor decreased tau phosphorylation and improved fear conditioning response [114]. In addition, IP administration of the flavonoid morin, a GSK3β inhibitor, in 3XTg-AD mice was also found to inhibit tau phosphorylation [115].…”

Section: Discussionmentioning

confidence: 99%

Small Molecule p75NTR Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in AβPPL/S Transgenic Mice

Nguyen

Shen

Griend

et al. 2014

JAD

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The p75 neurotrophin receptor (p75NTR ) is involved in degenerative mechanisms related to Alzheimer’s disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.

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Section: Discussionmentioning

confidence: 99%

Small Molecule p75NTR Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in AβPPL/S Transgenic Mice

Nguyen

Shen

Griend

et al. 2014

JAD

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“…Notwithstanding, there is not a single but multiple kinases involved in phosphorylating tau in vivo [41,42], raising the issue of whether reducing tau hyperphosphorylation will be more effective by targeting specific kinases or distinct groups of kinases [43]. Several tau kinases, including glycogen synthase kinase-3 (GSK-3), cyclin-dependent kinase 5 and micotubuleaffinity regulating kinase, among others, have all been implicated as potential kinase targets for tau therapeutics [44].…”

Section: The Role Of Phosphorylation In Tau Pathologymentioning

confidence: 99%

Further understanding of tau phosphorylation: implications for therapy

Medina

Ávila

2015

Expert Review of Neurotherapeutics

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Tau is a brain microtubule-associated protein that regulates microtubule structure and function. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders collectively referred to as tauopathies, the most common of which is Alzheimer's disease. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have unveiled novel important tau cellular functions that may also play a pivotal role in pathogenesis and render novel targets for therapeutic intervention. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, especially phosphorylation, which has significant implications for the development of novel therapeutic approaches in a number of neurodegenerative disorders.

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“…Diaminothiazoles is a CDK5 and GSK3β inhibitor. Diaminothiazoles decreased PHF‐1 immunoreactivity in two animal models of AD (3xTg‐AD and CK‐p25), showed neuroprotective effects, and helped memory recovery (Zhang, Hernandez, et al, ).…”

Section: Effects Of Cell Cycle Interfering Drugs On Ad Modelsmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

Cited by 42 publications

References 40 publications

Small Molecule p75NTR Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in AβPPL/S Transgenic Mice

Small Molecule p75NTR Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in AβPPL/S Transgenic Mice

Further understanding of tau phosphorylation: implications for therapy

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

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