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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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Abstract:

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.

Keywords: Alzheimer's disease; Amyloid- peptide; Neurotoxicity; Transgenic mice

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368908784423247

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: April 1, 2008

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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