THE LENGTH OF AMYLOID-BETA IN HEREDITARY CEREBRAL-HEMORRHAGE WITH AMYLOIDOSIS, DUTCH TYPE - IMPLICATIONS FOR THE ROLE OF AMYLOID-BETA-1-42 IN ALZHEIMERS-DISEASE

Citation
Em. Castano et al., THE LENGTH OF AMYLOID-BETA IN HEREDITARY CEREBRAL-HEMORRHAGE WITH AMYLOIDOSIS, DUTCH TYPE - IMPLICATIONS FOR THE ROLE OF AMYLOID-BETA-1-42 IN ALZHEIMERS-DISEASE, The Journal of biological chemistry, 271(50), 1996, pp. 32185-32191
Citations number
47
Categorie Soggetti
Biology
ISSN journal
00219258
Volume
271
Issue
50
Year of publication
1996
Pages
32185 - 32191
Database
ISI
SICI code
0021-9258(1996)271:50<32185:TLOAIH>2.0.ZU;2-#
Abstract
In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCEFWA -D), a genetic variant (E22Q) of amyloid beta (A beta) accumulates pre dominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life, A beta deposition in the neuropil occurs mainly in the form of preamyloid, Co ngo red negative deposits, while mature neuritic plaques and neurofibr illary tangles, hallmark lesions in Alzheimer's disease (AD), are char acteristically absent, A recent hypothesis regarding the patho genesis of AD states that A beta extending to residues 42-43 (as opposed to s horter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characteriz ed biochemically and immunohistochemically A beta from three cases of HCHWA-D to determine its length in vascular and parenchymal deposits, Mass spectrometry of formic acid-soluble amyloid, purified by size-exc lusion gel chromatography, showed that A beta 1-40 and its carboxyl-te rminal truncated derivatives were the predominant forms in leptomening eal and cortical vessels, A beta 1-42 was a minor component in these a myloid extracts, Immunohistochemistry with antibodies S40 and S42, spe cific for A beta ending at Val-40 or Ala-42, respectively, were consis tent with the biochemical data from vascular amyloid. In addition, par enchymal preamyloid lesions were specifically stained with S42 and wer e not labeled by S40, in agreement with the pattern reported for AD, D own's syndrome, and aged dogs, Our results suggest that in HCHWA-D the carboxyl-terminal A beta heterogeneity is due to limited proteolysis in vivo, Moreover, they suggest that A beta species ending at Ala-42 m ay not be critical for the seeding of amyloid formation and the develo pment of AD-like neuritic changes.