Neurotoxicity and Physicochemical Properties of Aβ Mutant Peptides from Cerebral Amyloid Angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) due to β-amyloid (Aβ) is one of the specific pathological features of familial Alzheimer's disease. Aβ mainly consisting of 40- and 42-mer peptides (Aβ40 and Aβ42) exhibits neurotoxicity and aggregative abilities. All of the variants of Aβ40 and Aβ42 found in CAA were synthesized in a highly pure form and examined for neurotoxicity in PC12 cells and aggregative ability. All of the Aβ40 mutants at positions 22 and 23 showed stronger neurotoxicity than wild-type Aβ40. Similar tendency was observed for Aβ42 mutants at positions 22 and 23 whose neurotoxicity was 50-200 times stronger than that of the corresponding Aβ40 mutants, suggesting that these Aβ42 mutants are mainly involved in the pathogenesis of CAA. Although the aggregation of E22G-Aβ42 and D23N-Aβ42 was similar to that of wild-type Aβ42, E22Q-Aβ42 and E22K-Aβ42 aggregated extensively, supporting the clinical evidence that Dutch and Italian patients are diagnosed as hereditary cerebral hemorrhage with amyloidosis. In contrast, A21G mutation needs alternative explanation with the exception of physicochemical properties of Aβ mutants. Attenuated total reflection-Fourier transform infrared spectroscopy spectra suggested that β-sheet content of the Aβ mutants correlates with their aggregation. However, β-turn is also a critical secondary structure because residues at positions 22 and 23 that preferably form two-residue β-turn significantly enhanced the aggregative ability.