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Contrasting In Vivo Effects of Two Peptide-Based Amyloid- Protein Aggregation Inhibitors in a Transgenic Mouse Model of Amyloid Deposition

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Previous studies have shown that 17,19,21-tri-N-methyl-A16-22 peptide (A16-22m), and a peptide analogue containing α,α-disubsituted amino acids (ααAA) in the hydrophobic core domain of A, termed AMY-1, effectively inhibited full-length A aggregation in vitro. To investigate the amyloid-modifying effects of these agents in vivo, we injected these compounds into the hippocampus of 13-month-old amyloid precursor protein (APP) transgenic mice, a model of amyloid deposition. After 7 days, brain tissues were stained for immunohistochemistry to detect total A and thioflavine-S (THIO-S) to measure A compact plaques. Both diffuse A deposits and compact amyloid plaques were significantly increased when injecting 0.3 nmol A16-22m compared to the PBS vehicle. The amyloid aggregation-modifying peptide AMY-1 showed a slight reduction of A deposition in the injection area at a dose of 0.3 nmol, but neuronal toxicity, measured by Fluoro-Jade and Nissl stains, appeared when higher doses (3 nmol) were tested. Our data indicate that, unlike observations reported in vitro, the A16-22m increased deposition of A in the brain of APP transgenic mice in vivo. Possible explanations for this outcome include unique influences of the brain environment and/or modification of A production or clearance by the administered agent. The AMY-1 peptide showed a trend for reducing A deposits, but led to toxicity at higher doses. These data emphasize the need for evaluating potential A aggregation inhibitors with in vivo models of amyloid deposition before assuming they will have benefit in treating Alzheimer's disease patients.
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Keywords: Alzheimer's disease; Amyloid- peptide; Neurotoxicity; Transgenic mice

Document Type: Research Article

Affiliations: 1: Alzheimer's Research Laboratory, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA 2: Department of Chemistry, Louisiana State University, Baton Rouge, LA, USA

Publication date: 2008-04-01

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