Biomedical subjects

F Prelli

Publications and source records attributed to F Prelli.

At least 19 recordsLinked to original sources

PubMed1992

A soluble form of prion protein in human cerebrospinal fluid: implications for prion-related encephalopathies.

The cellular prion protein (PrPc) is a 33-35 kDa sialoglycoprotein anchored to the external surface of neural and non-neural cells by a glycosyl phosphatidylinositol moiety. In addition, a secretory form of PrPc has been found in cell-free translation systems and in cell cultures. On this basis, we investigated human cerebrospinal fluid for the presence of soluble PrP and identified a protein whose molecular weight, antigenic determinants, N-terminal amino acid sequence and sensitivity to protease digestion corresponded to those of PrPc. In prion-related encephalopathies of humans and animals, the secretory form of PrPc might be converted into the abnormal isoform PrPSc and play a role in the dissemination of the disease process and amyloid formation.

Adolescent↗

PubMed1992

H chain V region sequences of three human monoclonal IgM with anti-myelin-associated glycoprotein activity.

The amino acid sequence corresponding to the V region H chain gene used by three monoclonal IgM directed to the myelin-associated glycoprotein (MAG) is presented. They all belonged to the VHIII variability subgroup, but each may well represent a new member of this family inasmuch as their homology with previously sequenced VHIII genes was less than 80%. Strikingly, there was no greater homology between the H chain V regions of the anti-MAG IgM. Partial amino acid sequence data indicated that these V regions were joined to as yet unidentified DH segments; however, two H chains used very similar DH, possibly indicating that this sequence was involved in the fine specificity of the IgM for MAG. All H chains included a JHIV region. These data, together with results obtained from the sequence of the three kappa L chains of the same IgM molecules (Mihaesco, E., H. Ayadi, N. Congy, M. C. Gendron, J. P. Roy, H. Heyermann, B. Frangione, and J. C. Brouet. 1989. J. Biol. Chem. 264:21481), indicate that the repertoire of VL and VH gene segments used by anti-MAG IgM is quite diverse, in contrast to previous structural data obtained for other human monoclonal IgM autoantibodies. Possibly, these differences reflect distinct pathogenesis.

Amino Acid Sequence↗

PubMed1992

Franklin's disease: Ig gamma 2 H chain mutant BUR.

The complete sequence of a gamma 2-H chain disease protein BUR is presented. This mutant, a dimer of a 348-residue chain, linked by four disulfide bridges, is composed of a complete V region, hinge, CH2, and CH3 domains. There is one deletion, the CH1 domain, which includes the cysteine residue bridging the H to L chain. Although the V region is encoded by the VHI and JHIII genes, it has several distinctions: methionine at position 11, two unique cysteine residues in the second complementarity determining region (CDR2), and three glycosylation sites, two of which are located in the CDR2 and CDR3 regions. These distinctive characteristics of BUR VH within the framework of a normal VHI may be affected by extensive somatic mutation or by a rare and previously unanalyzed VH gene.

Amino Acid Sequence↗

PubMed1991

Amyloid protein of Gerstmann-Sträussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N-terminal glycine at codon 58.

Gerstmann-Sträussler-Scheinker (GSS) disease is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. The GSS amyloid is immunoreactive to antisera raised against the hamster prion protein (PrP) 27-30. This is a proteinase K-resistant glycoprotein of 27-30 kd that is derived from an abnormal isoform of a neuronal glycoprotein of 33-35 kd designated PrPSc and is a molecular marker of amyloid fibrils isolated from animals with scrapie and humans with related disorders. We have purified and characterized proteins extracted from amyloid plaque cores isolated from two patients of the Indiana kindred of GSS disease. We found that the major component of GSS amyloid is an 11 kd degradation product of PrP, whose N-terminus corresponds to the glycine residue at position 58 of the amino acid sequence deduced from the human PrP cDNA. In addition, amyloid fractions contained larger PrP fragments with apparently intact N-termini and amyloid P component. These findings suggest that the disease process leads to proteolytic cleavage of PrP, generating an amyloidogenic peptide that polymerizes into insoluble fibrils. The N-terminal cleavage of PrP in GSS disease occurs at a tryptophan-glycine peptide bond identical to that cleaved by proteinase K in vitro to generate PrP 27-30 from hamster PrPSc at codon 90. Since no mutations of the structural PrP gene have been found in the Indiana family of GSS disease, it is conceivable that factors other than the primary structure of PrP play a crucial role in the process of amyloid formation and the development of clinical neurologic dysfunction.

Amino Acid Sequence↗

PubMed1991

Nodular cutaneous amyloidosis.

A nodular cutaneous amyloidosis biopsy specimen from a solitary nodule of a 75-year-old patient was characterized by amino terminal sequence analysis and was proved to be derived from immunoglobulin kIII light chain. Five years after the diagnosis of amyloidosis in the skin was made, a rectal biopsy demonstrated amyloid deposits in a blood vessel. It is suggested that nodular cutaneous amyloidosis is a slowly progressive systemic disease of the AL type, that manifest itself mainly in the skin.

Aged↗

PubMed1991

Characterization of high molecular weight amyloid A proteins.

Human amyloid A protein (AA) is usually composed of the NH2-terminal 76 amino acid residue of serum amyloid A protein (SAA), although lower and higher molecular weight fragments have been reported. We studied the primary structure of six AA proteins with molecular weights of 11 kDA-15kDA, as determined by SDS-PAGE. Automated Edman degradation of the intact purified proteins and sequence analysis of enzymatic peptides revealed that the AA proteins were composed of only 74 to 87 residues. Moreover, fragments of apolipoprotein E or histones 2a, 3 and 4 were associated with these AA molecules. Thus, AA heterogeneity may reflect diverse processing of the SAA precursor and a very close association with other proteins.

Amino Acid Sequence↗

PubMed1990

Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type.

Familial amyloidosis, Finnish type (FAF), is an inherited form of systemic amyloidosis clinically characterized by cranial neuropathy and lattice corneal dystrophy. We have demonstrated that the protein subunit isolated from amyloid fibrils shows considerable sequence identity with gelsolin, an actin-binding protein. We have purified the amyloid subunit from a second case and further analysed different fractions from the previous one. Sequence analysis shows that, in both cases, the amyloid subunit starts at position 173 of the mature molecule; it has a heterogeneous N-terminus and contains one amino acid substitution, namely asparagine for aspartic acid, at position 15 (gelsolin residue 187), that is due to a guanine-to-adenine transversion corresponding to nucleotide-654 of human plasma gelsolin cDNA. The substitution maps in a fragment with actin-binding activity and is located in a repetitive motif highly conserved among species. Thus FAF is the first human disease known to be caused by an internal abnormal degradation of a gelsolin variant. We designate this variant of gelsolin-associated amyloidosis 'Agel Asn-187'.

Aged↗

PubMed1990

Mutation in gelsolin gene in Finnish hereditary amyloidosis.

Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of familial amyloid polyneuropathy. The novel amyloid fibril protein found in these patients is a degradation fragment of gelsolin, an actin-binding protein. We found a mutation (adenine for guanine) at nucleotide 654 of the gelsolin gene in genomic DNA isolated from five FAF patients. This site is polymorphic since the normal allele was also present in all the patients tested. This mutation was not found in two unaffected family members and 11 normal controls. The A for G transition causes an amino acid substitution (asparagine for aspartic acid) that was found at position 15 of the amyloid protein. The mutation and consequent amino acid substitution may lead to the development of FAF.

Amino Acid Sequence↗

PubMed1990

Expression of a normal and variant Alzheimer's beta-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays.

Amyloid fibrils deposited in cerebral vessel walls in Dutch patients with hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) are formed by polymerization of a 39-residue peptide similar to the beta-protein of Alzheimer's disease, Down syndrome, sporadic cerebral amyloid angiopathy and normal aging. Sequence analysis of genomic DNA in HCHWA-D patients demonstrated a point mutation, cytosine for guanine at position 1852 of the precursor beta-protein gene, which causes a single amino acid substitution (glutamine for glutamic acid) corresponding to position 22 of the amyloid protein. The normal allele was also present in these patients. To examine the expression of normal and variant beta-protein alleles in HCHWA-D we analyzed all the tryptic peptides obtained from several amyloid fractions from leptomeningeal vascular walls. Amino acid sequence of two peptides (T3a and T3b) with identical amino acid composition revealed that T3a had glutamine and T3b had glutamic acid at position 22. Thus both the normal and variant Alzheimer's beta-protein alleles are expressed in vascular amyloid in HCHWA-D and may be detected by tryptic peptide mapping. Moreover, we have developed a diagnostic assay for high risk populations and prenatal evaluation that is based on the existence of the mutation.

Alzheimer Disease↗

PubMed1990

Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein.

Familial amyloidosis, Finnish type, is clinically characterized by cranial neuropathy and lattice corneal dystrophy. It is an autosomal dominant form of systemic amyloidosis with small deposits of congophilic material occurring in most tissues, particularly in association with blood vessel walls and basement membranes. Amyloid fibrils were extracted from the kidney of patient VUO, and rabbit antiserum raised against the 12 kDa purified amyloid subunit displayed strong immunohistochemical reactivity with the amyloid deposits. The amino terminal sequence of this 12 kDa amyloid protein (ATEVPVSWESFNNGD) showed homology with gelsolin (or actin depolymerizing factor), a 93 kDa plasma protein. The amyloid peptide is a degradation product, starting at position 173, of the gelsolin molecule.

Actins↗

PubMed1990

Amyloid in familial amyloidosis, Finnish type, is antigenically and structurally related to gelsolin.

Immunohistochemical studies of six patients with familial amyloidosis, Finnish type, showed that their amyloid deposits did not react with polyclonal antibodies against the amyloid proteins of other, established forms of systemic or cerebral amyloidosis. However, strong immunoreactivity was observed with rabbit antiserum raised against a low molecular weight purified amyloid subunit isolated from one of the patients. This immunoreactivity was abolished by absorption with the low molecular weight amyloid fraction. The amino terminal sequence of the amyloid protein subunit was homologous to gelsolin, an actin-modulating protein, and the amyloid deposits in tissues reacted with a monoclonal antibody against gelsolin. These studies show that the amyloid protein in familial amyloidosis, Finnish type, is not related to previously identified forms of amyloid, including prealbumin (transthyretin) variants, but represents a novel amyloidogenic protein related to gelsolin, a plasma and cytoplasmic protein.

Actins↗

PubMed1988

Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

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.

Alzheimer Disease↗

PubMed1988

Different processing of Alzheimer's beta-protein precursor in the vessel wall of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type.

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.

Alzheimer Disease↗

PubMed1988

Differences between vascular and plaque core amyloid in Alzheimer's disease.

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.

Alzheimer Disease↗

PubMed1988

Isolation and characterization of amyloid P component from Alzheimer's disease and other types of cerebral amyloidosis.

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.

Alzheimer Disease↗

PubMed1987

Degradation and deposition of amyloid AA fibrils are tissue specific.

The complete amino acid sequences of two related AA proteins (Mr 9700 and 5300) derived from thyroid tissue from a patient, NOR, with the autosomal recessive disease familial Mediterranean fever were determined. Heterogeneity found at position 52 indicates these proteins are fragments of two allelic or isotypic SAA precursor molecules similarly degraded at unusual sites and deposited in the thyroid. Degradation appears to be tissue and/or enzyme(s) specific since the carboxy terminus of both fragments is Ala-Ala and is different from other AA amyloid fibrils extracted from various tissues in different patients. Electron micrographic studies reveal these fragments retain the characteristics of native amyloid fibrils under physiological conditions even after exposure to dissociating agents.

Alleles↗

PubMed1987

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease.

Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related beta-protein. Silver stain-positive, "senile plaque-like" structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from the leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approximately equal to 4000 and its partial amino acid sequence to position 21 showed homology to the beta-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of beta-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.

Alzheimer Disease↗

PubMed1986

In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer's disease beta-protein.

Two synthetic peptides corresponding to the reported 28-residue sequence of Alzheimer's Disease beta-protein (SP28) and to residues 12-28 (SP17) were used to form fibrils in vitro. Synthetic fibrils bound Congo Red and closely resembled amyloid fibrils isolated from leptomeninges and senile plaques of Alzheimer's brain by electron microscopy. A polyclonal antiserum to SP28 specifically decorated both synthetic and native amyloid by colloidal gold immunoelectron microscopy. Amyloid fibrils isolated from tissue were insoluble on SDS-Polyacrylamide gels, and tended to aggregate while synthetic amyloid fibrils were completely solubilized, releasing only monomers of SP28 and SP17. Anti-SP28 immunostained cerebrovascular and plaque core amyloid, but not neurofibrillary tangles, in tissue section. Western blot analysis showed that anti-SP28 reacted with a 4 kDa band released from amyloid core-enriched preparations and leptomeninges. By contrast, a 16 kDa band corresponding to the tetramer of beta-protein was not recognized. These data suggest that as little as a 17 residue sequence of beta-protein may be required to form fibrils and that the complete sequence of the 4 kDa beta-protein may be important in determining insolubility and the formation of intermediate size polymers.

Alzheimer Disease↗