CHEMICAL CHARACTERIZATION OF A-BETA-17-42 PEPTIDE, A COMPONENT OF DIFFUSE AMYLOID DEPOSITS OF ALZHEIMER-DISEASE

A peptide corresponding to the amino acid sequence of Abeta17-42 (LVFF AEDVGSNKGAIIGLMVGGWIA) was isolated from Alzheimer Disease patient bra ins containing large deposits of diffuse-type amyloid. Brain homogenat es were lysed in SDS and submitted to high speed centrifugations. Abet a peptides were purified by size exclusion chromatography on Superose 12 and TSK 3000 SW columns. An Abeta peptide with M(r) of 3,000 was re covered that on automatic gas-phase Edman degradation yielded the amin o acid sequence of Abeta starting at residue 17 (Leu). The 3-kDa pepti de was subsequently hydrolyzed with trypsin and reacted with CNBr, and the resulting peptides were separated by reverse phase high pressure liquid chromatography and characterized by amino acid analyses, peptid e microsequencing, and mass spectrometry. Hydrolysis of beta-amyloid p recursor protein 695 at Lys612-Leu613 or at Lys16-Leu17 of its Abeta1- 42 derivative prevents the generation of neurotoxic Abeta filaments, t hus leading to the formation of Abeta17-42 localized in the diffuse am yloid deposits. An outstanding feature in the pathology of Alzheimer D isease is that the predominant Abeta peptides have their C termini at position 42, whether in the cores of the neuritic plaques, in the vasc ular walls, or in the diffuse deposits. Based on these observations, w e postulate that the accumulation of insoluble Abeta(N-42) in Alzheime r Disease is due to the anomalous processing of the C-terminal region.