K114 Inhibits A-beta Aggregation and Inflammation In Vitro and In Vivo in AD/Tg Mice
Merle G. Paule,
Debomoy K. Lahiri,
Ashlee Bell- Cohen,
Larry C. Schmued.
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 Aβ1-42
and Aβ1-40 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
Keywords: Alzheimer’s disease, amyloid-β aggregation, amyloid plaques, astrocytes, K114.
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