期刊
BIOCHEMISTRY
卷 44, 期 32, 页码 10810-10821出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi0508237
关键词
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资金
- NIA NIH HHS [P30 AG10133, R01 AG019795, R01 AG019795-08] Funding Source: Medline
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-beta (A beta) 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 A beta 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 A beta peptide species ending at residues 42 and 43 are the main A beta peptides deposited in brain parenchyma and LMD-CWPs in association with the PSEN1 V261I mutation. Full-length A beta 1-42 and A beta 1-43 peptide species were underrepresented. CWPs were not found to be associated with vessels and did not contain A beta 1-40 peptides, the main component of the vascular deposits. Although A beta 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 A beta 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 A beta peptide species. The generation and parenchymal deposition of highly insoluble amino-terminally truncated A beta peptides may play an important role in the pathogenesis of AD and must be taken into consideration in developing new diagnostic and therapeutic strategies.
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