Based on the recent discovery of co-localization of beta/A4 and cystatin C in cortical blood vessels of patients with cerebral hemorrhages due to sporadic amyloid angiopathy and patients with Alzheimer's disease we investigated the presence of these two proteins in the cortical blood vessels of patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch (n = 11) and the Icelandic (n = 2) type. The brains of three patients with sporadic cerebral amyloid angiopathy were also investigated. Blood vessels of the Dutch patients clearly showed immunostaining with beta/A4 as well as with cystatin C antibodies, whereas the blood vessels of Icelandic patients showed only staining with cystatin C. In one of the three sporadic amyloid angiopathy patients co-localization was shown as well. The co-localization of mutated beta/A4 with normal cystatin C in the Dutch patients suggests that cystatin C deposition occurs secondarily to beta/A4 deposition. This is probably also the case in sporadic amyloid angiopathy and Alzheimer's disease. Cystatin C deposition may play a role in the development of cerebral hemorrhages and leukoencephalopathy.
Cerebrovascular deposition of the amyloid beta-protein (Abeta) is a common pathologic event in patients with Alzheimer's disease (AD) and certain related disorders. Such an Abeta vascular deposition occurs primarily in the medial layer of the cerebral vessel wall in an assembled fibrillar state. These deposits are associated with several pathological responses, including degeneration of the smooth muscle cells in the cerebral vessel wall. Severe cases of cerebrovascular Abeta deposition are also accompanied by loss of vessel wall integrity and hemorrhagic stroke. Although the reasons for this pathological consequence are unclear, altered proteolytic mechanisms within the cerebral vessel wall may be involved. We analyzed cerebral Abeta deposition in brains with AD and Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) on the basis of two amyloid species of Abeta(40) and Abeta(42/43) using specific monoclonal antibodies. Compared to Abeta deposition in senile plaques, the molecular composition of Abeta was distinguishable, indicating that the Abeta(40) species is the main component for vascular amyloid. Furthermore, we found Abeta(42/43) immunoreactivity was also much increased in amyloid angiopathy of all cases with HCHWA-D. Taken together, amyloid angiopathy in HCHWA-D may share an Abeta(42)-driven deposition mechanism with plaque amyloid, resulting in enhanced Abeta(40) deposition.