azure-c and Alzheimer-Disease

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.

Topics: Alzheimer Disease; Animals; Benzodioxoles; Cholinesterase Inhibitors; Cholinesterases; Curcumin; Humans; Molecular Targeted Therapy; Neurofibrillary Tangles; Neuroprotective Agents; Phosphorylation; Plaque, Amyloid; Protein Aggregation, Pathological; Protein Processing, Post-Translational; Quinazolines; Receptors, N-Methyl-D-Aspartate; tau Proteins; Thiadiazoles

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder affecting millions of people worldwide. Therefore, finding effective interventions and therapies is extremely important. AD is one of over 20 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable fibrils, including neurofibrillary tangles, and oligomers. The smaller, soluble and dynamic tau oligomers have been shown to be more toxic with more proficient seeding properties for the propagation of tau pathology as compared to the fibrillar Paired Helical Filaments (PHFs). Therefore, developing small molecules that target and interact with toxic tau oligomers can be beneficial to modulate their aggregation pathways and toxicity, preventing progression of the pathology. In this study, we show that Azure C (AC) is capable of modulating tau oligomer aggregation pathways at micromolar concentrations and rescues tau oligomers-induced toxicity in cell culture. We used both biochemical and biophysical in vitro techniques to characterize preformed tau oligomers in the presence and absence of AC. Interestingly, AC prevents toxicity not by disassembling the oligomers but rather by converting them into clusters of aggregates with nontoxic conformation.

Topics: Alzheimer Disease; Azure Stains; Cell Line, Tumor; Disease Progression; Humans; Neurofibrillary Tangles; tau Proteins; Tauopathies

Alzheimer's disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aβ-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD.

Topics: Alzheimer Disease; Animals; Azure Stains; Drosophila Proteins; HEK293 Cells; Humans; Larva; Methylene Blue; Neuromuscular Junction; Phosphorylation; Protein Serine-Threonine Kinases; Synapses; tau Proteins

Alzheimer disease is characterized by the abnormal aggregation of amyloid beta peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid beta oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid beta aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid beta monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Humans; Plaque, Amyloid; Protein Structure, Quaternary; Thermodynamics