Towards Diagnosis and Treatment of Alzheimer's Disease

摘要

More and more evidence shows that Alzheimer's disease belongs to the family of conformational diseases characterized by protein self-association and tissue deposition as amyloid fibrils. As recently shown, monoclonal antibodies interact at strategic sites where conformational changes of proteins are initiated, stabilizing the protein and preventing further aggregation. These data, and the recent performance of such antibodies in transgenic mice as a model for human diseases, convert the immunological concept into a therapeutic strategy for the development of vaccination against such diseases. Here we describe a new immunization procedure against p-amyloid plaques using as antigen the EFRH peptide displayed on the surface of the filamentous phage. Antibodies to the epitope EFRH, representing residues 3-6 within the P-amyloid peptide, were found to modulate its in vitro solubility and aggregation. The EFRH phage induced effective anti-ag-gregating antibodies in transgenic mice that recapitulate the amyloid plaques and vascular pathology of Alzheimer's disease. The immunization led to a considerable reduction in the number of p-amyloid plaques found in the brains of the sacrificed transgenic mice. However, effective means are required for in vivo brain imaging to monitor changes in the plaque burden of patients' brains. We propose anti-P-amyloid antibodies displayed on genetically engineered filamentous phages as a specific probe to monitor amyloid plaque formation in living patients. Intranasal administration of filamentous phage as a delivery vector of anti-P-amyloid antibody fragment into brains of Alzheimer's APP transgenic mice enables in vivo targeting of p-amyloid plaques. The plaques were co-visualized both by Thioflavin-S and fluorescent-labeled antibodies in the olfactory bulb and hip-pocampal regions, which correlate with early plaque formation. The genetically engineered filamentous bacteriophage proved to be an efficient and non-toxic viral delivery vector to the brain, offering an obvious advantageover mammalian vectors. Future studies will determine if coupling-up radiopharmaceuticals to phage carrying antibodies would detect brain amyloid deposits in vivo. The feasibility of these novel strategies may have clinical potential for diagnosis and treatment of Alzheimer's disease and other brain disorders.