RESUMO
Alzheimer's disease (AD) is characterized, in part, by atrophy of the adult brain and increased presence of extracellular amyloid-beta (Aß) plaques. Previous studies in our lab have shown that peripheral inflammation can lead to increased central Aß and deficits in learning and memory. In order to determine whether Aß accumulation in the brain is responsible for the learning deficits, we attempted to decrease peripheral production of Aß in order to reduce central Aß accumulation. It has previously been shown that Aß is produced in large quantities in the liver, and is transferred across the blood-brain barrier (BBB). Recent research has shown that peripheral treatment with imatinib methanesulfonate salt (IM), known to interfere with the interaction between gamma (γ)-secretase and the γ-secretase activating protein (GSAP), decreases the cleavage of peripheral amyloid precursor protein into Aß. Because IM poorly penetrates the BBB, we hypothesized that co-administration of IM with LPS would decrease peripheral production of Aß in the presence of LPS-induced inflammation, leading to a decrease in Aß accumulation in the hippocampus. We show that peripheral IM treatment eliminates hippocampal Aß elevation that follows LPS-induced peripheral inflammation. Importantly, IM also eliminates the cognitive impairment seen following seven consecutive days of LPS administration, implicating Aß peptides as a likely cause of these cognitive deficits.
