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Biomedical subjects

B Frangione

Publications and source records attributed to B Frangione.

At least 109 records · Page 6Linked to original sources
PubMed1995

Tau protein directly interacts with the amyloid beta-protein precursor: implications for Alzheimer's disease.

The simultaneous presence of intracellular neurofibrillary tangles (NFT) and extracellular senile plaques in Alzheimer's disease (AD) suggests that the two lesions could be synergistically interrelated. However, although the main protein components of NFT and senile plaques, tau (tau) and amyloid beta-protein, respectively, are well characterized, the molecular mechanisms responsible for their deposition in lesions are unknown. We demonstrate, using four independent techniques, that tau directly interacts with a conformation-dependent domain of the amyloid beta-protein precursor (beta PP) encompassing residues beta PP714-723. The putative tau-binding domain includes beta PP717 mutation sites that are associated with familial forms of AD. Our findings strongly suggest that NFT and senile plaques, often thought of as independent structures, may play a role in each other's formation during the pathogenesis of AD.

Alzheimer Disease↗
PubMed1995

Non-Alzheimer's disease amyloidoses of the nervous system.

Amyloidosis and prionosis are disorders of protein conformation. The general mechanisms involved in amyloidogenesis are reviewed here. Recent progress in the molecular pathogenesis of cerebral amyloids is illustrated by three genetic disorders: hereditary amyloid angiopathies of Icelandic and Dutch origins and Gerstmann-Sträussler-Scheinker disease.

Aged↗
PubMed1995

Early onset Alzheimer's disease in a South American pedigree from Argentina.

We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed beta amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the beta amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease.

Adult↗
PubMed1995

Gerstmann-Sträussler-Scheinker disease and the Indiana kindred.

Gerstmann-Sträussler-Scheinker disease is an autosomal dominant disorder with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs, and dementia. The patients present with symptoms in the third to sixth decade of life and the mean duration of illness is five years. Mutations at codons 102, 105, 117, 145, 198 and 217 of the open reading frame of the prion protein gene have been associated with GSS disease. As a result of the mutations, a substitution at the corresponding residues of the prion protein occurs, or as in the case of the STOP mutation at codon 145, a truncated protein is produced. Neuropathologically, the common denominator is a cerebral prion protein amyloidosis; however, there is significant variability in the pattern of amyloid deposition in regions of the central nervous system among reported families. Amyloidosis coexists with severe spongiform degeneration in patients with the mutation at codon 102, and with neurofibrillary degeneration in the patients with mutation at codons 145, 198 and 217. The development of a transmissible spongiform encephalopathy in animals inoculated with brain tissue from affected subjects with mutation at codon 102 suggests that in some forms of genetically-determined Gerstmann-Sträussler-Scheinker disease, and particularly those characterized by severe spongiosis, amyloidogenesis and production of an infectious "agent" occur concomitantly via mechanisms that are only partially understood.

Amyloid↗
PubMed1995

Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D): clinicopathological studies.

Clinical and neuropathological findings are reported in 63 patients with hereditary cerebral haemorrhage with amyloid angiopathy. Patients had mostly recurrent strokes, and at least 80% of these were haemorrhages. Almost a third of the patients died within a year of their first and only recorded haemorrhage, half of them within two weeks. This angiopathy was restricted to the cerebral and cerebellar cortex and its covering leptomeninges. As the most important consequence, haemorrhagic infarcts and haemorrhages occurred in the subcortical white matter--that is, the region most vulnerable to impaired cortical circulation. Further development of these subcortical lesions gives rise to the fatal haemorrhages seen at necropsy. In so far as dementia occurs this is likely to result from multiple microinfarcts or haemorrhages. In most cases preamyloid lesions or diffuse plaques and early plaques were seen. No other type of plaque or neurofibrillary degeneration was found. The plaques occur in conjunction with the angiopathy, but may not occur even when the angiopathy is severe. In one patient plaques were totally absent. Angiopathy and plaques may be the result of the same mutation, the expression of which is governed by tissue factors or phenotypic differences between individual subjects.

Adult↗
PubMed1995

Conformational mimicry in Alzheimer's disease. Role of apolipoproteins in amyloidogenesis.

Several apolipoproteins are known to be closely associated with amyloid fibrillogenesis. Serum amyloid A, apolipoprotein (apo) AII and apo A1 are each deposited as biochemically distinct forms of amyloid. Late-onset Alzheimer's disease is linked to one isotype of apo E, apo E4. Apo E and apo E4 in particular have been shown to modulate amyloid fibril formation by amyloid-beta peptides in vitro. Furthermore, the carboxy terminus of apo E has been shown to be a constituent of plaque amyloid. We show immunohistochemically and electron microscopically the presence of apo A1 in senile plaques. The intact apo A1 can itself form amyloid-like fibrils in vitro that are Congo Red positive. We propose that some proteins when misfolded can propagate this misfolding to identical units, either autocatalytically or to other proteins that are induced to fold into the same abnormal conformation. This conformational mimicry may initiate and/or augment fibrillogenesis in Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma.

The amyloid fibrils of Alzheimer's neuritic plaques and cerebral blood vessels are mainly composed of aggregated forms of a 39 to 44 amino acids peptide, named amyloid beta (A beta). A similar although soluble form of A beta (sA beta) has been identified in plasma, cerebrospinal fluid and cell culture supernatants, indicating that it is produced under physiologic conditions. We report here that sA beta in normal human plasma is associated with lipoprotein particles, in particular to the HDL3 and VHDL fractions where it is complexed to ApoJ and, to a lesser extent, to ApoAI. This was assessed by immunoprecipitation experiments of purified plasma lipoproteins and lipoprotein-depleted plasma and confirmed by means of amino acid sequence analysis. Moreover, biotinylated synthetic peptide A beta 1-40 was traced in normal human plasma in in vitro experiments. As in the case of sA beta, biotinylated A beta 1-40 was specifically recovered in the HDL3 and VHDL fractions. This data together with the previous demonstration that A beta 1-40 is taken up into the brain via a specific mechanism and possibly as an A beta 1-40-ApoJ complex indicate a role for HDL3- and VHDL-containing ApoJ in the transport of the peptide in circulation and suggest their involvement in the delivery of sA beta across the blood-brain barrier.

Amino Acid Sequence↗
PubMed1994

Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer's amyloid beta.

Amyloid beta (A beta) is a fibrillar component in Alzheimers' disease amyloid deposits and a soluble peptide (sA beta) normally present in body fluids. We have recently reported that the blood-brain barrier (BBB) has a capability to control cerebrovascular sequestration and transport of circulating sA beta. In this study, we examined whether two circulating amyloid-associated proteins shown to bind sA beta, apolipoproteins J (apo J) and E (apo E), can cross the BBB alone and/or complexed to a synthetic peptide homologous to a major form of sA beta, sA beta 1-40. Brain perfusion experiments in guinea pigs showed significant uptake of both apo J and sA beta 1-40-apo J complexes. In contrast, blood-brain transport of sA beta 1-40-apo E was negligible, while apo E had a limited access across the BBB, indicating that the apo E found within the brain is produced locally. It is concluded that sA beta 1-40 binding to apo J and apo E results in significant (> 100-fold) difference in brain uptake of their respective complexes. We hypothesize that in normal brain apo J facilitates sA beta transport.

Amyloid beta-Peptides↗
PubMed1994

Amyloid fibrils in Gerstmann-Sträussler-Scheinker disease (Indiana and Swedish kindreds) express only PrP peptides encoded by the mutant allele.

Gerstmann-Sträussler-Scheinker (GSS) disease is a cerebral amyloidosis linked to mutations of the PRNP gene. We previously reported that the amyloid protein in the Indiana kindred of GSS is an internal fragment of prion protein (PrP). To investigate whether this fragment originates only from mutant or from both mutant and wild-type PrP, we have characterized amyloid proteins purified from patients of the Indiana and Swedish GSS families. These patients were heterozygous for the Met-Val polymorphism at PRNP codon 129 and carried a mutation at PRNP codon 198 (Phe-->Ser) and codon 217 (Gln-->Arg), respectively. The smallest amyloid subunit was a 7 kDa peptide spanning residues approximately 81 to approximately 150 in the Indiana patient and approximately 81 to approximately 146 in the Swedish patient. In both patients, only Val was present at position 129. Since Val-129 was in coupling phase with Ser-198 and Arg-217, our findings indicate that only the mutant PrP is involved in amyloid formation in both kindreds.

Amino Acid Sequence↗
PubMed1994

Characterization of a novel processing pathway for Alzheimer's amyloid beta precursor protein.

Amyloid beta (A beta) is a normal proteolytic fragment of a large precursor protein (beta PP) which undergoes altered conformation, leading to fibril formation. Two main beta PP processing pathways have been described, and we are now reporting the characterization of a third beta PP pathway. A membrane-associated 16 kDa component identified in human platelets isolated from normal donors. Based on size, immunoreactivity and amino acid sequence analysis, the fragment is a C-terminal beta PP component which starts at position 642 (APP770 numbering) and contains the intact A beta sequence. The presence of this novel pathway of beta PP processing in resting platelets suggest that it occurs as a normal event.

Alzheimer Disease↗
PubMed1994

Familial Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles.

Patients affected with Gerstmann-Sträussler-Scheinker disease from two families, one from Indiana and one of Swedish origin, have been studied. The patients are clinically characterized by cerebellar ataxia, extrapyramidal signs, and dementia. Accumulation of amyloid deposits and neurofibrillary tangles are the most conspicuous neuropathologic features. In the patients from the Indiana family, the amyloid contains an 11-kDa peptide, an amyloidogenic degradation product of the prion protein. The neurofibrillary tangles are composed of paired helical filaments and immunoreact with antibody to A68, an abnormally phosphorylated form of the microtubule-associated protein tau. In these families, the disease is caused by a point mutation in the PRNP gene. In the Indiana family, the mutation is at codon 198, and in the Swedish family at codon 217.

Aged↗
PubMed1994

Unifying features of systemic and cerebral amyloidosis.

Amyloidosis is a generic term for a group of clinically and biochemically diverse diseases that are characterized by the deposition of an insoluble fibrillar protein in the extracellular space. Over 16 biochemically distinct amyloids are known. Despite this diversity, all amyloids have a particular ultrastructural and tinctorial appearance, a beta-pleated sheet structure, and are codeposited with a group of amyloid-associated proteins. The most common amyloidosis is Alzheimer's disease (AD), where A beta is the main component of the amyloid. Recently it has been found that A beta exists as a normal soluble protein (sA beta) in biological fluids. This links AD more closely to some of the systemic amyloidoses, where the amyloid precursor is found in the circulation normally. Numerous mutations have been found in the A beta precursor (beta PP) gene, associated with familial AD. Many mutations are also found in some of the hereditary systemic amyloidoses. For example, over 40 mutations in the transthyretin (TTR) gene are associated with amyloid. However, both A beta and TTR related amyloid deposition can occur with no mutation. The pathogenesis of amyloid is complex, and appears to be associated with genetic and environmental risk factors that can be similar in the systemic and cerebral amyloidoses.

Alzheimer Disease↗