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Effects Of Imatinib Methanesulfonate On Inflammation-Induced Amyloid-Beta Production
Bisson, Courtney
Bisson, Courtney
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2013
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2013-05-03
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by atrophy of the adult brain and increased presence of extracellular amyloid-beta (A-beta) plaques and intracellular tau tangles. Presence of these truncated or misfolded proteins results in altered cellular signaling, oxidative stress, and ultimately to cell death. Chronic inflammation has been implicated in the onset and progression of these AD pathologies. Previous studies in our lab have shown that peripheral inflammation can lead to increased central A-beta and deficits in learning and memory. In order to determine if the A-beta accumulation in the brain is responsible for the learning deficits, we attempted to decrease peripheral production of A-beta in order to reduce central A-beta accumulation. It has previously been shown that A-beta is produced in large quantities in the liver, and is transferred across the blood brain barrier. Recent research has shown that peripheral treatment with imatinib methanesulfonate salt (IM), a form of the anti-cancer drug Gleevecâ„¢ and known to interfere with the interaction between gamma-secretase and the gamma-secretase activating protein (GSAP), decreases the cleavage of peripheral amyloid precursor protein into A-beta. Because IM poorly penetrates the blood brain barrier, we hypothesized that co-administration with LPS would decrease peripheral production of A-beta leading to a decrease in A-beta accumulation in the hippocampus. We show here that peripheral IM treatment eliminates the elevation in hippocampal A-beta following LPS induced peripheral inflammation. More importantly, IM eliminates the cognitive impairment seen following 7 consecutive days of LPS administration, implicating A-beta peptides as the cause of these performance deficits.
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Biology