Tau

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Alectos Therapeutics Announces FDA Orphan Drug Designation for MK-8719: An Investigational Small-molecule OGA Inhibitor for Treatment of Progressive Supranuclear Palsy

Advances Novel Tau-directed Strategy for Treating Neurodegenerative Disease Phase 1 Clinical Trial Completed Vancouver, British Columbia (April 20, 2016) – Alectos Therapeutics Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OGA inhibitor MK-8719 for the treatment of progressive supranuclear palsy (PSP). Alectos also announced completion of [...]

April 20th, 2016|Tags: , , , , , |

Preclinical Data Disclosed for Tau PET Tracer MK-6240: A Potential Clinical Biomarker for OGA Inhibitor MK-8719

Apr 18, 2016 – Alectos Therapeutics partner Merck, known as MSD outside the U.S. and Canada, today disclosed preclinical data for potential clinical biomarker [18F]-MK-6240, a highly selective and specific tau PET tracer useful as an imaging agent for quantification of neurofibrillary tangles (NFTs). A pathological hallmark of Alzheimer's disease, as well as several other neurodegenerative [...]

April 18th, 2016|Tags: , , , , , , |

Discovery of [18F]-MK-6240: A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate discovery of new disease modifying therapeutics targeting tau pathology. Herein we present the [...]

April 18th, 2016|Tags: , , , , , |

Alectos Announces Preclinical Results in TAPP Mouse Model of Alzheimer’s Disease

Oct 26, 2014 – Alectos today announced publication of preclinical studies showing that pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in the TAPP mouse model of Alzheimer’s disease. For details, see: Yuzwa, S.A. et al. Mol Neurodegener 9:42 (2014).

October 26th, 2014|Tags: , , , , , , , |

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice

BACKGROUND: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of [...]

October 26th, 2014|Tags: , , , , , , , |

The emerging link between O-GlcNAc and Alzheimer disease

Regional glucose hypometabolism is a defining feature of Alzheimer disease (AD). One emerging link between glucose hypometabolism and progression of AD is the nutrient-responsive post-translational O-GlcNAcylation of nucleocytoplasmic proteins. O-GlcNAc is abundant in neurons and occurs on both tau and amyloid precursor protein. Increased brain O-GlcNAcylation protects against tau and amyloid-β peptide toxicity. Decreased O-GlcNAcylation [...]

October 21st, 2014|Tags: , , , , , , , , , , |

Chronic O-β-N-acetylglucosaminylase inhibition with Thiamet-G prevents tau pathology and hyperactivity in rTg4510 mice

Background: The abnormal hyperphosphorylation of the microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer's disease (AD) and aggregation of hyperphosphorylated tau into neurofibrillary tangles is a hallmark brain lesion in AD. Besides kinases and phosphatases tau phosphorylation is regulated by O-GlcNAcylation, a posttranslational modification of proteins on the serine or threonine residues with [...]

September 6th, 2014|Tags: , , , , , |

O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer’s disease and beyond

Alzheimer disease (AD) is a growing problem for aging populations worldwide. Despite significant efforts, no therapeutics are available that stop or slow progression of AD, which has driven interest in the basic causes of AD and the search for new therapeutic strategies. Longitudinal studies have clarified that defects in glucose metabolism occur in patients exhibiting [...]

April 24th, 2014|Tags: , , , , , , , , |

O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers

The aggregation of the microtubule-associated protein tau into paired helical filaments to form neurofibrillary tangles constitutes one of the pathological hallmarks of Alzheimer's disease. Tau is post-translationally modified by the addition of N-acetyl-D-glucosamine O-linked to several serine and threonine residues (O-GlcNAc). Previously, increased O-GlcNAcylation of tau has been shown to block the accumulation of tau [...]

January 18th, 2014|Tags: , , , |

Increasing brain protein O-GlcNAcylation mitigates breathing defects and mortality of Tau.P301L mice

The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher [...]

December 23rd, 2013|Tags: , , , , |