New diagnostic method for Alzheimer's disease based on the toxic conformation theory of amyloid beta

摘要

Recent investigations suggest that soluble oligomeric amyloid beta (A beta) species may be involved in early onset of Alzheimer's disease (AD). Using systematic proline replacement, solid-state NMR, and ESR, we identified a toxic turn at position 22 and 23 of A beta 42, the most potent neurotoxic A beta species. Through radicalization, the toxic turn can induce formation of the C-terminal hydrophobic core to obtain putative A beta 42 dimers and trimers. Synthesized dimer and trimer models showed that the C-terminal hydrophobic core plays a critical role in the formation of high molecular weight oligomers with neurotoxicity. Accordingly, an anti-toxic turn antibody (24B3) that selectively recognizes a toxic dimer model of E22P-A beta 42 was developed. Sandwich enzyme-linked immunosorbent assay with 24B3 and 82E1 detected a significantly higher ratio of A beta 42 with a toxic turn to total A beta 42 in cerebrospinal fluid of AD patients compared with controls, suggesting that 24B3 could be useful for early onset of AD diagnosis.