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
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
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.