Identification of the shortest Aβ-peptide generating highly specific antibodies against the C-terminal end of amyloid-β42

Alzheimer's disease (AD) is characterized by neurofibrillary tangles, consisting of hyperphosphorylated tau protein and senile plaques, which are consisting mainly of amyloid-beta (A beta). Attempts to generate a safe vaccine against A beta rely on both B- and T-cell epitopes within the neurotoxic peptide A beta 1-42. This, however, poses a risk for an inflammatory and/or autoimmune response against A beta-peptides in the brain. To overcome such risks we wanted to identify the shortest C-terminal A beta-peptide that would induce antibodies selectively recognizing the C-terminal end of A beta 42. Immunization with this antigen should result in a non-inflammatory Th2 immune response and the T-cell response should be against a T-cell epitope covalently attached to the small A beta-peptide. Antigen constructs were made by the ligand presenting assembly (LPA) technology, comprising dimeric presentation of short A beta-peptides ending at amino acid 42 in connection with potent T-cell epitopes. Mice were immunized with antigen constructs using different adjuvants, and sera from mice were tested to characterize the generated immune response. Immunization with Keyhole limpet hemocyanin (KLH)-A beta(37-42) resulted in generation of IgG1 antibodies specific for the A beta 42 C-terminal end, indicating a Th2-response. The T-cell mediated response was predominantly against T-cell epitopes in KLH. The antibodies stained senile plagues specifically in brain tissue from AD patients. Thus, KLH-A beta(37-42) was able to induce a non-inflammatory and highly specific antibody response against A beta 42. (C) 2011 Elsevier Ltd. All rights reserved.