The length of Amyloid-β in Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch Type

Abstract

In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), a genetic variant (E22Q) of amyloid β (Aβ) accumulates predominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life. Aβ deposition in the neuropil occurs mainly in the form of preamyloid, Congo red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark lesions in Alzheimer's disease (AD), are characteristically absent. A recent hypothesis regarding the pathogenesis of AD states that Aβ extending to residues 42-43 (as opposed to shorter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characterized biochemically and immunohistochemically Aβ 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-exclusion gel chromatography, showed that Aβ 1-40 and its carboxyl-terminal truncated derivatives were the predominant forms in leptomeningeal and cortical vessels. Aβ 1-42 was a minor component in these amyloid extracts. Immunohistochemistry with antibodies S40 and S42, specific for Aβ ending at Val-40 or Ala-42, respectively, were consistent with the biochemical data from vascular amyloid. In addition, parenchymal preamyloid lesions were specifically stained with S42 and were not labeled by S40, in agreement with the pattern reported for AD, Down's syndrome, and aged dogs. Our results suggest that in HCHWA-D the carboxyl-terminal Aβ heterogeneity is due to limited proteolysis in vivo. Moreover, they suggest that Aβ species ending at Ala-42 may not be critical for the seeding of amyloid formation and the development of AD-like neuritic changes.