amyloid-beta-peptides and isoleucyl-lysyl-valyl-alanyl-valine

Alzheimer's disease (AD) is one of the most common dementia, which is not effectively cured to date. Amyloid-beta (Abeta) deposition cascade and disintegrity of brain extracellular matrix (ECM) scaffold attribute to the progress of AD. Thus, it maybe an effective way to treat AD by altering the processing of amyloid precursor protein (APP) and regaining the integrity of ECM. The peptide amphiphile (PA) with a laminin epitope isoleucine-lysine-valine-alanine-valine (IKVAV) (IKVAV-PA) can be trigged into ECM in vivo. In addition, IKVAV-PA could significantly improve cognitive impairment with remarkable increase of endoneurogensis in the hippocampus, as well as reduction of burden of amyloid plaque in the brain.. We used heterozygous AbetaPPswe/PS1dE9 double transgenic mice as the animal model of AD. After 1 week of initial stereotaxic administration into bilateral hippocampus, the mice were subjected to the Morris Water Maze (MWM) test. At the end of MWM test, immunohistochemical staining, Western blot and real-time polymerase chain reaction (PCR) were performed in mice.. Here we showed that IKVAV-PA significantly improved cognitive impairment accompanying with reducing the burden of Abeta plaques, as well as the levels of soluble Abeta1-40 and Abeta1-42 in the cortex and hippocampus after 2 weeks of initial administration into bilateral hippocampus. Further examination demonstrated that IKVAV-PA also altered the processing of APP via inhibiting the gene expression of beta-secretase (BACE1), as well as improving the gene expression of insulin-degrading enzyme (IDE) and neprilysin (NEP).. Our data suggest that IKVAV-PA may serve as an alternative therapeutic intervention for treating the learning and memory losses in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cerebral Cortex; Disease Models, Animal; Hippocampus; Insulysin; Laminin; Male; Maze Learning; Mice, Inbred C57BL; Mice, Transgenic; Nanofibers; Neprilysin; Peptide Fragments; Presenilin-1; Random Allocation

The peptide amphiphile (PA) with a laminin epitope IKVAV (IKVAV-PA) can be trigged into three-dimensional nanostructures in vivo. Application of IKVAV-PA to the injured spinal cord resulted in significant functional improvement in rodents with remarkable axonal regeneration at the lesion site. Here we showed that injection of IKVAV-PA into the hippocampus of a transgenic (Tg) mice model of Alzheimer's disease (AD) significantly improved cognitive impairment, accompanied by an enhanced neurogenesis in the hippocampus. Further examination demonstrated that IKVAV-PA injections also significantly reduced the levels of soluble Aβ1-40, Aβ1-42, and amyloid-beta (Aβ) plaques in these brains. Our data suggest that IKVAV-PA may serve as a potential therapeutic intervention for the learning and memory losses in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cell Differentiation; Cognition Disorders; Hippocampus; Laminin; MAP Kinase Signaling System; Maze Learning; Memory; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nanofibers; Neural Stem Cells; Neurogenesis; Neurons; Peptide Fragments; Plaque, Amyloid