Hereditary cerebral hemorrhage with amyloidosis of Dutch type (HCHWA-D) is an autosomal dominant form of accelerated brain fibrillogenesis. It 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 lesions in brain parenchyma resembling diffuse plaques. Distinct from Alzheimer's disease (AD) these deposits only occasionally are surrounded by dystrophic neurites and neurofibrillary tanges are absent. We have shown that the amyloid extracted from leptomeninges in HCHWA-D is a 39/40 residues peptide which is similar to the amyloid ( (A() obtained from AD, Down's syndrome and aged brains. This self-aggregating peptide is an internal proteolytic fragment of a larger membrane glycoprotein (PP, encoded by a single gene in chromosome 21. We detected a point mutation at codon 693 which causes a substitution of Glu for Gln at position 22 of A(. The mutation segregates with the disease and induces accelerated fibril formation in vitro. Our preliminary observations that A(17-42 (the """"""""non-amyloidogenic"""""""" p3 fragment) might be a component of the diffuse plaques and that PS1 is present in both lesions in HCHWA-D, a disease not linked to chromosome 14, are puzzling. Our central interest lies in the apparent link between neurodegeneration and amyloidogenic proteins and in the determination of genetic and/or environmental factors that initiate and perpetuate amyloid formation. We postulate that HCHWA-D is a distinct entity that shares pathological similarities with AD and propose HCHWA-D as a model for cerebral amyloidosis in man. Better biochemical understanding of this pathological process and amyloidogenesis in humans and in animal models would facilitate therapeutic intervention in AD and aging. This proposal is directed to answer the following questions:
Aim 1 : Why diffuse plaques do not evolve to senile plaques in HCHWA-D? What is the biochemical composition of diffuse plaques and vascular amyloid deposits in HCHWA-D? What is the role of presenilins in amyloidogenesis? Aim 2: Can we inhibit, delay and/or revert the amyloidogenesis process designing amyloid analogs containing similar hydrophobicity but low propensity to adopt (-sheet conformation? Aim 3: Is the HCHWA-D model supportive of the hypothesis of the soluble origin of the A( deposited in brain lesions? Which is the role of the A( mutants in vascular localization, vascular sequestration, blood-to-brain and brain-to-blood transport in the in vivo perfusion model in guinea pigs?
