amyloid-beta-peptides and Amyloidosis--Familial

To report the clinical, genetic, neuroimaging, and neuropathologic studies of patients with the hereditary cerebral hemorrhage with amyloidosis linked to the APP E693K mutation.. Case series. Clinical details and laboratory results were collected by direct evaluation and previous medical records. DNA analysis was carried out in several affected subjects and healthy individuals. Neuropathologic examination was performed in 2 subjects.. Southern Lombardy, Italy. Patients Individuals with and without amyloidosis in 4 unrelated Italian families (N = 37). Main Outcome Measure Genotype-phenotype relationship.. The affected individuals presented with recurrent headache and multiple strokes, followed by epilepsy and cognitive decline in most of them. The disease was inherited with an autosomal dominant trait and segregated with the APP E693K mutation. Neuroimaging demonstrated small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, and leukoaraiosis. Amyloid-beta immunoreactivity was detected in the wall of leptomeningeal and parenchymal vessels and in the neuropil, whereas phosphorylated tau, neurofibrillary changes, and neuritic plaques were absent.. These findings expand the number of APP mutations linked to hereditary cerebral hemorrhage with amyloidosis, reinforcing the link between this phenotype and codon 693 of APP.

Topics: Aged; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis, Familial; Apolipoprotein E4; Cerebral Hemorrhage; Family Health; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Glutamic Acid; Humans; Italy; Lysine; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Peptide Fragments

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.

Topics: Amyloid beta-Peptides; Amyloidosis, Familial; Animals; Cerebral Hemorrhage; Cerebrovascular Circulation; Chlorocebus aethiops; COS Cells; Humans; Mice; Mutation; Netherlands; Peptide Fragments; Sweden; Transfection