Faculty Bibliography

Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke

The predominant protein of cerebrovascular and plaque core amyloid in Alzheimer's disease, Down's syndrome, hereditary hemorrhage with amyloidosis--Dutch type, sporadic cerebral amyloid angiopathy, and age-related amyloidosis is a unique polypeptide, called beta protein. The length of the plaque amyloid protein was reported to be 42-43 residues, but the complete length of the cerebral vascular amyloid is not known. To clarify this issue, amyloid fibrils from the leptomeninges of an Alzheimer's disease patient were isolated and the primary structure determined. The complete sequence of cerebrovascular beta-amyloid protein, although homologous to the plaque core amyloid protein previously reported, has 39 residues instead of 42. Amino terminal heterogeneity is present but minimal, and it is three residues shorter at the carboxy terminus. These differences are similar to those found in two cases of hereditary hemorrhage with amyloidosis--Dutch type. The differences between vascular and plaque beta-amyloid may reflect diverse processing of the beta protein precursor in the vessel wall and brain parenchyma due to tissue-specific endopeptidases

Rheumatoid factors (RFs) in humans have been studied intensively because of their association with autoimmune and lymphoproliferative diseases. Many human IgM-RFs express cross-reactive idiotypes (CRIs) and have homologous light chains, some of which are encoded by a single V kappa gene, termed V kappa 325. However, although antibody activity generally requires the interaction between heavy and light chain variable regions, much less is known about structural relationships among RF heavy chains. To delineate further the structural and genetic basis of RF autoantibody synthesis, we generated 'sequence-dependent' reagents specific for the human heavy and kappa light chain subgroups, and used them to analyze a panel of 27 monoclonal RFs. In addition, these proteins were tested for the expression of a heavy chain-associated CRI (G6), and a light chain-associated CRI (17.109). The results showed that most 17.109-reactive RFs contain heavy chains of the VHI subgroup, which bear the G6 idiotypic marker. However, among the 14 17.109-reactive RFs, two have heavy chains of the VHII subgroup, and another two contain heavy chains of the VHIII subgroup. Previously, we have shown that 17.109 is a phenotypic marker of the human V kappa 325 gene. Accordingly, these results demonstrate that the same human V kappa gene can combine with several VH genes from different VH gene subgroups to generate RF activity

This article describes 136 patients with hereditary cerebral haemorrhages; all patients belonged to families (originally) resident in Katwijk (The Netherlands). Cases of hereditary cerebral haemorrhage have also been reported in NW-Iceland, and in the Dutch coastal village of Scheveningen. Katwijk is a Dutch fishing-village, located 20 miles north of Scheveningen. These 136 cases were encompassed in three large pedigrees, and the disorder followed an autosomal dominant mode of inheritance. No connection between the pedigrees from Iceland, Scheveningen and Katwijk has as yet been established. In our series, sclerosis with amyloid deposits could be observed in roughly a quarter of the small arteries and arterioles in the cerebral cortex and the covering arachnoid. The pathological vessels were irregularly distributed in areas and clusters, possibly leading to superficial cerebral infarcts and, secondarily, to haemorrhages. Our findings are identical with those described in patients from Scheveningen, but different from the Icelandic group. In addition to some differences in the age at onset and in the distribution of the angiopathy, it has recently been demonstrated that the amyloid in our patients is constituted by a microprotein which shows a homology to the beta-protein in Alzheimer's disease and Down's syndrome, while the amyloid in Icelandic cases is formed by an aggregation of cystatin C (gamma trace). An unexpected finding in most of our patients is the accumulation of senile plaque-like lesions in the cerebral cortex. We did not observe Alzheimer's fibrillary tangles in any of our cases

The presence of amyloid P-component (AP) within cerebral amyloid deposits was investigated by means of biochemical and immunocytochemical methods. Immunoperoxidase on formalin-fixed, paraffin-embedded tissue sections from Alzheimer's Disease, Down's Syndrome, asymptomatic age-related cerebral amyloidosis, sporadic cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Icelandic type, and hereditary cerebral hemorrhage with amyloidosis-Dutch type revealed the presence of AP in the affected vessel walls in all cases, and in parenchymal deposits resembling neuritic plaques of Alzheimer's disease, sporadic cerebral amyloid angiopathy, and hereditary cerebral hemorrhage with amyloidosis-Dutch type. A short digestion of tissue sections with pepsin was required for immunodetection of AP in these latter structures. After extraction of leptomeningeal amyloid fibrils, AP was characterized by sodium dodecyl sulfate-polyacrylamide-gel electrophoresis, Western blot, gel chromatography, and partial amino acid sequencing. Our results indicate that: (a) AP from cerebral amyloidosis has similar biochemical properties and homologous amino terminal sequence to AP from systemic amyloidosis; (b) AP is associated to a variety of brain amyloid deposits regardless of their chemical nature. The presence of AP, a serum protein, within the brain parenchyma points to an impairment of the blood-brain barrier in these diseases

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is an autosomal-dominant type of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes. Amyloid fibrils from the leptomeninges of two patients were isolated and the primary structure determined. The complete sequence of the amyloid protein shows homology to the vascular (beta-protein) and plaque amyloid (A4-protein) obtained from Alzheimer's Disease. However, it is three residues shorter (39 instead of 42) than that reported for the plaque amyloid. The difference at the carboxy terminal may reflect specific degradation that occurs in the vessel wall and not in the brain parenchyma

Protein Rou is a human IgA2 myeloma protein that carries the isoallotype marker n A2m(2). Partial amino acid sequence of its H chain (alpha) shows that the hinge region and the CH2 domain are homologous to alpha 2-chain and the CH1 and the CH3 domains homologous to alpha 1. Moreover, the CH1 domain contains the H-L disulfide bond identical to alpha 1. It is concluded that Rou H chain is a hybrid molecule caused by a recombination between alpha 1 and alpha 2 genes. The recombination event occurred between alpha 1-exon 1 and alpha 2-exon hinge and corresponds to position 222-223 of the alpha-chain

Two electrophoretically homogeneous immunoglobulins were detected in the serum of a patient with multiple myeloma. The heavy chains were of different classes (gamma 1 and gamma 2). The light chains of both were kappa, but had different electrophoretic mobilities on polyacrylamide gels. Amino acid sequence analysis, carbohydrate determinations, and biosynthetic experiments indicated that the difference seen in their electrophoretic mobility was due to the glycosylation of one but not the other kappa-chain. The primary structure of both chains demonstrated that they both used a V kappa 1 and a J kappa 2 gene segment and the same C kappa allele, Km(1,2), and that both contained the same junctional three amino acid deletion. However, they varied by 19 amino acids in the first 94 amino terminal residues encoded for by the V kappa gene, with some of the substitutions requiring two base changes in the appropriate codons. Moreover, the malignant 'clones' producing the two proteins differed in their responses to chemotherapy. These data indicate that, although the two clones producing the serum proteins were different at the time of study, they may have arisen from the same precursor clone