Adv Protein Chem Struct Biol. 2012;88:133-52.
Treatment with Aβ42 Binding d-Amino Acid Peptides Reduce Amyloid Deposition and Inflammation in APP/PS1 Double Transgenic Mice.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
One of the two characteristic pathological hallmarks of Alzheimer’s disease (AD) are neuritic plaques. The sequence of events leading to the extracellular deposition of amyloid β (Aβ) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relationship between aggregation and deposition of Aβ by using peptides that bind to Aβ as antifibrillization treatments in APP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brain of these AD-model mice for 4weeks with one of the three small d-amino acid peptides (i.e., D1, D3, or D3-FITC) that were designed to bind specifically to Aβ42, and examined the subsequent improvement in cognitive deficits after 3weeks and analyzed amyloid deposition in the brain following the behavioral analysis. Cognitive deficits are similar comparing control and D3-treated mice, but D1-treated mice are slightly, but significantly, impaired. In contrast, there is a substantial improvement in the cognitive deficits in the animals treated with D3-FITC, compared to the other mice. In contrast, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3, compared to the other groups of mice. Furthermore, the amount of activated microglia and astrocytes surrounding Aβ deposits is dramatically reduced in both the D3- and D3-FITC-treated mice. Our findings demonstrate that treatments with a high-affinity Aβ-42-binding d-amino acid peptide significantly decrease Aβ deposits and the associated inflammatory response. Together, this suggests that aggregation likely plays an important role in the deposition of Aβ protein in APP/PS1 transgenic mice and that antiaggregation treatments with d-peptides may be successful in AD patients.