MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.

Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ, the pathogenic self-aggregating species of Aβ.

Results: MEDI1814 reduces free Aβ without impacting Aβ in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration.

Unbiased kidney-centric molecular categorization of chronic kidney disease as a step towards precision medicine.

Current classification of chronic kidney disease (CKD) into stages using indirect systemic measures (estimated glomerular filtration rate (eGFR) and albuminuria) is agnostic to the heterogeneity of underlying molecular processes in the kidney thereby limiting precision medicine approaches. To generate a novel CKD categorization that directly reflects within kidney disease drivers we analyzed publicly available transcriptomic data from kidney biopsy tissue. A Self-Organizing Maps unsupervised artificial neural network machine-learning algorithm was used to stratify a total of 369 patients with CKD and 46 living kidney donors as healthy controls.

Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM.

SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle.

Background And Purpose: In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ.

Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes.

Background: Preferential utilization of fatty acids for ATP production represents an advanced metabolic phenotype in developing cardiomyocytes. We investigated whether this phenotype could be attained in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and assessed its influence on mitochondrial morphology, bioenergetics, respiratory capacity and ultra-structural architecture.

Methods And Results: Whole-cell proteome analysis of day 14 and day 30-CMs maintained in glucose media revealed a positive influence of extended culture on mitochondria-related processes that primed the day 30-CMs for fatty acid metabolism.

The Conundrum of GSK3 Inhibitors: Is it the Dawn of a New Beginning?

Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer's disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials.

Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3Δ25bpIntronic Deletion in South Asian Descendants.

Importance: The genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp.

Thymosin Beta-4 Is Elevated in Women With Heart Failure With Preserved Ejection Fraction.

Background: Thymosin beta-4 (TB4) is an X-linked gene product with cardioprotective properties. Little is known about plasma concentration of TB4 in heart failure (HF), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB4 in HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared to non-HF controls.

Beyond amyloid: getting real about nonamyloid targets in Alzheimer's disease.

For decades, researchers have focused primarily on a pathway initiated by amyloid beta aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early during the course of disease, even prior to the onset of clinical symptoms. Thus, targeting amyloid in patients with mild to moderate Alzheimer's disease (AD), as past failed clinical trials have done, may be insufficient to halt further disease progression.

AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans.

Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase-3β (GSK3β) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies.

Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.

Glycogen synthase kinase-3β, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3β localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance.

Mutations in nicastrin protein differentially affect amyloid beta-peptide production and Notch protein processing.

The γ-secretase complex is responsible for intramembrane processing of over 60 substrates and is involved in Notch signaling as well as in the generation of the amyloid β-peptide (Aβ). Aggregated forms of Aβ have a pathogenic role in Alzheimer disease and, thus, reducing the Aβ levels by inhibiting γ-secretase is a possible treatment strategy for Alzheimer disease. Regrettably, clinical trials have shown that inhibition of γ-secretase results in Notch-related side effects.

A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases.

Background: The signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons.

A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation.

Our aging society is confronted with a dramatic increase of patients suffering from tauopathies, which include Alzheimer disease and certain frontotemporal dementias. These disorders are characterized by typical neuropathological lesions including hyperphosphorylation and subsequent aggregation of TAU protein and neuronal cell death. Currently, no mechanism-based cures are available.

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.

Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride.

AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test.

The mechanism by which lithium exerts either its anti-manic or antidepressant effects remains to be fully elucidated. Although lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3) at concentrations that are relevant for treatment of bipolar disorder, it is unclear whether GSK-3-related mechanisms are responsible for its therapeutic effects in the treatment of this disease. We report that AR-A014418 (a selective GSK-3 inhibitor) induces behavioural changes that are consistent with the effects of antidepressant medications.

Glycogen synthase kinase 3: a drug target for CNS therapies.

Abstract Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke.

Expression of an altered form of tau in Sf9 insect cells results in the assembly of polymers resembling Alzheimer's paired helical filaments.

Tau is the main component of the paired helical filaments (PHFs), aberrant structures that develop in the brain of Alzheimer's disease (AD) patients and other tauopathies like frontotemporal dementia and parkinsonism associated to chromosome 17 (FTDP-17). Previous work has shown that tau overexpression in Sf9 insect cells results in the formation of long cytoplasmatic extensions as a consequence of microtubule stabilization and bundling. Throughout this work, we have taken studies in this system further by overexpression of an altered form of tau characteristic of FTDP-17, which includes three mutations (G272V, P301L and R406W) and biochemically behaves as a hyperphosphorylated form of the protein, with the aim of developing an in vitro model which would favour the formation of tau aggregates.

Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease.

Tauopathies, including Alzheimer's disease, are neurodegenerative disorders in which tau protein accumulates as a consequence of alterations in its metabolism. At least three different types of alterations have been described; in some cases, an aberrant mRNA splicing of tau exon 10 occurs; in other cases, the disorder is a consequence of missense mutations and, in most cases, aberrant tau hyperphosphorylation takes place. Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the etiology of Alzheimer's disease and other tauopathies.

Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418.

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3.

GSK3beta signalling: casting a wide net in Alzheimer's disease.

Glycogen synthase kinase-3beta (GSK3beta) is a kinase that plays a pivotal role in numerous cellular functions from modulation of microtubule dynamics and cell death. It also affects higher functions such as cognition and mood. Deregulation of GSK3beta activity in the adult brain is implicated in several CNS disorders, such as affective disorders, schizophrenia, stroke and neurodegenerative diseases, such as Alzheimer's disease (AD).

Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis.

Caspase-3 is an intracellular cysteine protease, activated as part of the apoptotic response to cell injury. Its interest as a therapeutic target has led many to pursue the development of inhibitors. To date, only one series of nonpeptidic inhibitors have been described, and these have limited selectivity within the caspase family.

Interactions between GSK3beta and caspase signalling pathways during NGF deprivation induced cell death.

Withdrawal of NGF (NGF-W) in PC12 cells leads to caspase and GSK3beta activation which results in cell death. Our recent findings suggest that inhibition of GSK3beta promotes PC12 cell survival after NGF-W. To determine whether these pathways interact from a signalling perspective, we compared the effects of BAF (a general caspase inhibitor), Li+ (a GSK3beta inhibitor) and insulin on NGF-W induced PC12 cell death.