Hereditary cerebral hemorrhage with amyloidosis of Dutch type (HCHWA-D), also designated familial cerebral amyloid angiopathy, is an autosomal dominant form of brain amyloidosis. The disease is characterized by extensive amyloid deposition in the small leptomeningeal arteries and cortical arterioles, which leads to cerebral hemorrhage and early death. In most cases, there are also amyloid deposits in brain parenchyma, resembling early senile plaques. Distinct from Alzheimer's disease (AD), these amyloid plaques are not intermingled with or surrounded by dystrophic neurites, and neurofibrillary tangles are absent. We have shown that the amyloid extracted from leptomeninges in HCHWA-D, is a 39-residues peptide, which is similar to the Beta-amyloid protein (AP) that forms vascular amyloid in AD and Down's syndrome. This self-aggregating peptide is an abnormal proteolytic fragment of a much larger cell surface receptor protein (APP) encoded by a gene located in chromosome 21. We also detected a point mutation in the DNA segment coding for the AP in two patients, that caused the substitution of Gln for Glu at position 22. Although segregation studies are still under way, it is likely that this mutation is the primary defect in HCHWA-D, since no such substitution has previously been observed in AP in normal humans, AD or familial AD patients. We postulate that i) HCHWA-D is a distinct entity that shares pathological similarities with AD, and ii) point mutation in the APP gene and/or different origin and processing of the APP in particular tissues are responsible for the differences between the two. We propose: I: To complete the sequence of the APP gene in Dutch patients. II: To study the segregation in different families. III: To isolate and characterize the soluble and membrane-bound forms of the normal and variant APP from serum, platelets, cerebral spinal fluid and vessel walls. IV: To produce amyloid fibril formation in vitro via synthetic peptides homologous to the Beta-protein and Dutch variant. V: To develop an animal model by constructing transgenic mice and test whether the mutation causes amyloid deposition in the brain.
