ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, wherein, the accumulation of amyloid beta (Abeta) peptide as cytotoxic oligomers leads to neuropathologic changes. Transgenic mice with brain Abeta plaques immunized with aggregated Abeta have reduced amyloid burden and improved cognitive functions. However, such active immunization in humans led to a small but significant occurrence of meningoencephalitis in 6% AD volunteers due to Abeta induced toxicity. In an attempt to develop safer alternative vaccines, the design of a highly soluble peptide homologous to Abeta (Abeta-EK), that has a reduced amyloidogenic potential while maintaining the major immunogenic epitopes of Abeta is reported. More importantly, this homologue has been shown to be non-toxic, as this peptide failed to exert any observable effect on erythrocytes. The results of the present study suggests that immunization with non-toxic Abeta derivative may offer a safer therapeutic approach to AD, instead of using toxic Abeta fibrils.
Subject(s)
Alzheimer Vaccines/immunology , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/immunology , Mutation , Alzheimer Disease/immunology , Alzheimer Disease/prevention & control , Alzheimer Vaccines/administration & dosage , Amino Acid Sequence , Amino Acid Substitution , Amyloid beta-Peptides/metabolism , Animals , Antibody Specificity , Benzothiazoles , Cell Shape/drug effects , Cell Shape/immunology , Enzyme-Linked Immunosorbent Assay , Erythrocytes/cytology , Erythrocytes/drug effects , Erythrocytes/immunology , Humans , Molecular Sequence Data , Protein Binding , Rabbits , Thiazoles/metabolismABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia affecting the elderly. Treatment for effective cure of this complex neurodegenerative disease does not yet exist. In AD, otherwise soluble, monomeric form of amyloid beta (Abeta) peptide converts into toxic, fibrillar form rich in beta-sheet content. Several immunological approaches that prevent this conversion of Abeta into pathological form or that accelerate its clearance are being actively pursued worldwide. As part of these attempts, we report here, the design and characterization of a non-amyloidogenic homologue of Abeta (Abeta-KEK). We demonstrate that this peptide is helical in nature and retains the immunoneutralizing epitopes of native Abeta. More importantly, Fab fragments of the polyclonal anti-Abeta-KEK antibodies interfere with formation of Abeta fibrils as well as dissociate the preformed Abeta aggregates in vitro. These results suggest that non-amyloidogenic Abeta-KEK may serve as a safer alternative vaccine for Alzheimer's disease.
