Contrasting In Vivo Effects of Two Peptide-Based Amyloid-β Protein Aggregation Inhibitors in a Transgenic Mouse Model of Amyloid Deposition
Autor: | Qingyou Li, Marcia Gordon, Marcus A. Etienne, Robert P. Hammer, Dave Morgan Ph.D. |
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Jazyk: | angličtina |
Rok vydání: | 2008 |
Předmět: | |
Zdroj: | Cell Transplantation, Vol 17 (2008) |
Druh dokumentu: | article |
ISSN: | 0963-6897 1555-3892 |
DOI: | 10.3727/096368908784423247 |
Popis: | Previous studies have shown that 17,19,21-tri-N-methyl-Aβ16-22 peptide (Aβ16-22m), and a peptide analogue containing α,α-disubsituted amino acids (ααAA) in the hydrophobic core domain of Aβ, termed AMY-1, effectively inhibited full-length Aβ 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 Aβ and thioflavine-S (THIO-S) to measure Aβ compact plaques. Both diffuse Aβ deposits and compact amyloid plaques were significantly increased when injecting 0.3 nmol Aβ16-22m compared to the PBS vehicle. The amyloid aggregation-modifying peptide AMY-1 showed a slight reduction of Aβ 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 Aβ16-22m increased deposition of Aβ 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 Aβ production or clearance by the administered agent. The AMY-1 peptide showed a trend for reducing Aβ deposits, but led to toxicity at higher doses. These data emphasize the need for evaluating potential Aβ aggregation inhibitors with in vivo models of amyloid deposition before assuming they will have benefit in treating Alzheimer's disease patients. |
Databáze: | Directory of Open Access Journals |
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