The accumulation of amyloid-β (Aβ) in the brain is believed to have a pivotal role in Alzheimer disease (AD) pathology. Kumar et al. now provide in vivo evidence that Aβ may also perform a protective antimicrobial function.
Medical Xpress New mouse model could revolutionize research in Alzheimer's disease Medical Xpress Alzheimer's disease, the primary cause of dementia in the elderly, imposes a tremendous social and economic burden on modern society.
Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being.
Brivaracetam (Briviact- UCB) for Partial-onset seizures Pimavanserin tartrate (Nuplazid - Acadia) for hallucinations and delusions associated with Parkinson's disease psychosis Gallium Ga 68 dotatate (Netspot - AAA) for neuroendocrine tumours
A recent article identified five key technical determinants that make substantial contributions to the outcome of drug R&D projects (Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework.
Two reports show big increases in R&D spending among both biotech and pharmaceutical drug developers.In an annual review of the biotech sector, analysts at EY (formerly Ernst & Young) found that biotech companies spent US$40.1 billion on R&D...
STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-aminehydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.
Substantial evidence from both genetic and toxin induced animal and cellular models and postmortem human brain tissue indicates that mitochondrial dysfunction plays a central role in pathophysiology of the neurodegenerative disorders including Parkinson's disease (PD), and Huntington's disease (HD). This review discusses the emerging understanding of the role of mitochondrial dysfunction including bioenergetics defects, mitochondrial DNA mutations, familial nuclear DNA mutations, altered mitochondrial fusion/fission and morphology, mitochondrial transport/trafficking, altered transcription and increased interaction of pathogenic proteins with mitochondria in the pathogenesis of PD and HD. This review recapitulates some of the key therapeutic strategies applied to surmount mitochondrial dysfunction in these debilitating disorders. We discuss the therapeutic role of mitochondrial bioenergetic agents such as creatine, Coenzyme-Q10, mitochondrial targeted antioxidants and peptides, the SIRT1 activator resveratrol, and the pan-PPAR agonist bezafibrate in toxin and genetic cellular and animal models of PD and HD. We also summarize the phase II-III clinical trials conducted using some of these agents. Lastly, we discuss PGC-1α, TORC and Sirtuins as potential therapeutic targets for mitochondrial dysfunction in neurodegenerative disorders. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'
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