B. Frangione - Academia.edu (original) (raw)

Papers by B. Frangione

American Journal Of Pathology

Neuroscience letters, Jan 17, 1995

Synthetic peptides containing the sequence of Alzheimer's amyloid-beta peptide (A beta) spont... more Synthetic peptides containing the sequence of Alzheimer's amyloid-beta peptide (A beta) spontaneously form amyloid-like fibrils in vitro, and have been extensively used to study the factors that modulate fibrillogenesis. Contradictory observations have been reported regarding the neurotoxicity of A beta and the influence of some A beta-binding proteins on in vitro A beta amyloid formation. In this study, we show that A beta 1-40 synthetic peptides obtained from different suppliers, have significantly distinct fibrillogenic properties. No differences were detected in the chemical structure or in the initial assembly state by mass spectroscopy, reverse-phase high performance liquid chromatography and denaturing or non-denaturing gel electrophoresis. However, there was a direct correlation between the ability of soluble peptides to form amyloid and their percentage of beta-sheet structure, as determined by electron microscopy, fluorescence associated to thioflavine T bound to amylo...

Nature, Jan 24, 1999

Familial British dementia (FBD), previously designated familial cerebral amyloid angiopathy-Briti... more Familial British dementia (FBD), previously designated familial cerebral amyloid angiopathy-British type, is an autosomal dominant disorder of undetermined origin characterized by progressive dementia, spasticity, and cerebellar ataxia, with onset at around the fifth decade of life. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Here we report the identification of a unique 4K protein subunit named ABri from isolated amyloid fibrils. This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor that is encoded by a novel gene, BRI, located on chromosome 13. A single base substitution at the stop codon of this gene generates a longer open reading frame, resulting in a larger, 277-residue precursor. Release of the 34 carboxy-terminal amino acids from the mutated precursor generates the ABri amyloid subunit. The mutation creates a cutting site for the re...

Proceedings of the National Academy of Sciences, 2000

Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autos... more Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.

Neuroscience Letters, 1992

Microscopy Research and Technique, 2000

Journal of Biological Chemistry, 1995

The main component of Alzheimer's amyloid deposits, A beta, has been found also as a solu... more The main component of Alzheimer's amyloid deposits, A beta, has been found also as a soluble (sA beta) normal constituent of biological fluids and cell culture supernatants. Whether or not sA beta is the immediate precursor of A beta, it is clear that peptides with the same amino acid sequence can have both fibrillar and non-fibrillar conformations. The interconversion mechanism from one form to another is presently under intensive investigation. We have previously described that (i) a synthetic peptide A beta 1-40 immobilized on affinity matrices was able to retrieve apolipoprotein J (apoJ) from plasma and cerebrospinal fluid; and (ii) the interaction of sA beta with apoJ occurs in vivo, as demonstrated by the ability of anti-apoJ to co-precipitate sA beta from normal cerebrospinal fluid. We have characterized the binding between A beta 1-40 and apoJ and found that the interaction is saturable, specific, and reversible. The dissociation constant of 2 x 10(-9) M is indicative of high affinity binding. The stoichiometry of the reaction is 1:1; apoJ has five times more affinity for fresh A beta 1-40 than for the aggregated peptide. Competitive inhibition studies carried out with apolipoprotein E (isoforms E2, E3, and E4), transthyretin, vitronectin, and alpha 1-antichymotrypsin indicate that the complex apoJ.A beta 1-40 cannot be dissociated by any of these competitors at physiologic concentrations. The data strongly suggest that apoJ plays an important role as a carrier protein for sA beta.

$Research paper thumbnail of Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic xray diffraction pattern$

Biochemical and Biophysical Research Communications, 1987

Annals of the New York Academy of Sciences, 2000

Annals of the New York Academy of Sciences, 2006

Annals of Neurology, 2000

The American Journal of Pathology, 1998

We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) iso... more We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases. First, our data show that PrPC proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrPC in brain is blocked by inhibitors of metalloproteases. Third, differences in PrPC proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrPSc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrPSc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype. This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility.

Alzheimer's & Dementia, 2010

The Biochemical journal, 1995

A central event in Alzheimer's disease is the conformational change from normally circulating... more A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replac...

The Journal of biological chemistry, Jan 25, 1985

The amino acid sequence of human tissue amyloid P component (AP) extracted by a modified method f... more The amino acid sequence of human tissue amyloid P component (AP) extracted by a modified method from the spleen of a patient with primary idiopathic amyloidosis was determined. AP is a glycoprotein composed of a pair of noncovalently bound pentameric discs with a subunit size of 23-25 kDa. Each subunit consists of 204 residues, a single disulfide bridge linking Cys 36 to Cys 95, and a carbohydrate moiety attached to Asn 32. The precursor of AP is the serum amyloid protein (SAP). The primary structure of AP presented here differs from the amino acid sequence of SAP previously reported, but is identical to the amino acid sequence of mature SAP deduced from the nucleotide sequence of complementary DNA clones. It shares 52% homology with the amended sequence of human C-reactive protein, an acute phase protein, and 68% homology with the Syrian hamster "female protein," another acute phase protein whose response is modulated by sex steroids. AP/SAP, C-reactive protein, and femal...

Acta neuropathologica, 2000

Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common t... more Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipopriotein E (APOE)-epsilon4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide f...

Nature medicine, 1998

Inhibition of cerebral amyloid beta-protein deposition seems to be an important target for Alzhei... more Inhibition of cerebral amyloid beta-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as beta-sheet breakers. Here we demonstrate a 5-residue peptide that inhibits amyloid beta-protein fibrillogenesis, disassembles preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the beta-sheet breaker peptide significantly reduces amyloid beta-protein deposition in vivo and completely blocks the formation of amyloid fibrils in a rat brain model of amyloidosis. These findings may provide the basis for a new therapeutic approach to prevent amyloidosis in Alzheimer's disease.

FEBS letters, Jan 12, 1997

Soluble A beta (Sa beta) is normally present at a low concentration in human plasma and cerebrosp... more Soluble A beta (Sa beta) is normally present at a low concentration in human plasma and cerebrospinal fluid. Although the factors involved in the regulation of Sa beta plasma levels are still unknown, we have explored its excretion in the urine as one of the possible homeostatic mechanisms. The presence of Sa beta in the urine was investigated via immunoprecipitation experiments with anti-A beta antibodies followed by detection and identification by immunoblot, MALDI mass spectrometry and sequence analysis. Soluble A beta (4.3 kDa) immunoreactivity was present in the urine of normal donors, Down's syndrome individuals as well as in patients with renal disorders exhibiting glomerular or mixed proteinuria. Edman degradation of the immunoprecipitated material yielded the intact A beta N-terminus and mass spectra analysis indicated the existence of a major component at mlz 4327, corresponding to the molecular mass of A beta1-40. Semiquantitative data obtained from the immunoprecipit...