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K114 Inhibits A-beta Aggregation and Inflammation In Vitro and In Vivo in AD/Tg Mice

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Abstract:

Alzheimer’s disease (AD) is the most common age related human neurodegenerative disorder. The major histopathological characteristics of the AD brain are extracellular amyloid-beta (Aβ) peptide loaded plaques and intraneuronal neurofibrillary tangles made of phosphorylated tau proteins. Amyloid plaques consist primarily of aggregated Aβ 1-42 and Aβ 1-40 peptides. The aim of our current study was to test novel ligands/agents with the potential to disrupt or inhibit the aggregation of Aβ peptide, specifically K114, (trans,trans)-1-bromo-2,5-bis(4-hydroxystyryl)benzene, which was initially developed as a potential positron emission tomography (PET) ligand for the in vivo detection of amyloid plaques. Systemic administration of K114 has been shown in the AD/transgenic (Tg) mouse model to be capable of crossing the blood-brain barrier (BBB) and be colocalized with amyloid plaques. In this study we determined whether K114 has the potential to inhibit Aβ aggregation in vitro in AD/Tg mice and also tested, in vivo, whether chronic daily orally administered K114 has any therapeutic potential as evidenced by inhibition or reduction of the deposits of amyloid aggregates in the brains of AD/Tg mice. Our results demonstrated that K114 strongly blocked, in vitro, the aggregation of Aβ peptide in the amyloid plaques of AD/Tg mouse brain. Systemic treatment with K114 was also effective in significantly reducing the deposits of amyloid plaques in the brains of living transgenic AD mice. Additionally, K114 significantly inhibited the typically observed plaque associated astrocytic activation, as revealed by GFAP immunohistochemistry, suggesting possible anti-inflammatory properties.

Keywords: Alzheimer’s disease; K114; amyloid plaques; amyloid-β aggregation; astrocytes

Document Type: Research Article

Publication date: March 1, 2014

More about this publication?
  • Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
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