Amino-Terminally Truncated Aβ Peptide Species Are the Main Component of Cotton Wool Plaques

• Published in: Biochemistry (Easton) Vol. 44; no. 32; pp. 10810 - 10821
• Main Authors: Miravalle, Leticia, Calero, Miguel, Takao, Masaki, Roher, Alex E, Ghetti, Bernardino, Vidal, Ruben
• Format: Journal Article
• Language: English
• Published: American Chemical Society 16.08.2005
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi0508237

Cotton wool plaques (CWPs) are round lesions that lack a central amyloid core. CWPs have been observed in individuals affected by early-onset familial Alzheimer disease (FAD) associated with mutations in the presenilin 1 (PSEN1) gene. Here we present the characterization of the amyloid-β (Aβ) peptides deposited in the brain of an individual affected by FAD carrying the novel missense (V261I) mutation in the PSEN1 gene. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to determine the Aβ peptide species present in the cerebral and cerebellar cortices, in leptomeningeal vessels, and in CWPs isolated by laser microdissection (LMD). Our results indicate that amino-terminally truncated Aβ peptide species ending at residues 42 and 43 are the main Aβ peptides deposited in brain parenchyma and LMD-CWPs in association with the PSEN1 V261I mutation. Full-length Aβ1−42 and Aβ1−43 peptide species were underrepresented. CWPs were not found to be associated with vessels and did not contain Aβ1−40 peptides, the main component of the vascular deposits. Although Aβ deposits were present mostly in the form of CWPs in the cerebral cortex and as diffuse deposits in the cerebellar cortex, a similar array of amino-terminally truncated Aβ peptide species was seen in both cases. The biochemical data support the concept that parenchymal and vascular amyloid deposits are associated with a different array of Aβ peptide species. The generation and parenchymal deposition of highly insoluble amino-terminally truncated Aβ peptides may play an important role in the pathogenesis of AD and must be taken into consideration in developing new diagnostic and therapeutic strategies.