Diffuse senile plaques: amorphous or fibrous?
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Alzheimer Disease↗
Biomedical subjects
F Tagliavini
Publications and source records attributed to F Tagliavini.
Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study.
Creutzfeldt-Jakob disease (CJD) is a prion-related subacute encephalopathy producing widespread neuronal degeneration and spongiform pathological changes, especially in the neocortex. Progressive dementia, motor signs and electroencephalographic (EEG) alterations characterize the full stage of the disease. A series of eight 24-hour polygraphic recordings were carried out in the last 3 months of life of a 68-year-old female patient affected by CJD that was confirmed neuropathologically. Genetic classification demonstrated this patient to have a sporadic form of the disease. The polygraphic recordings demonstrated three types of EEG findings, as follows: 1) sustained pseudoperiodic discharges (SPD), characterized by long-lasting diffuse sequences of slow sharp waves or di- or triphasic slow waves recurring at 0.5- to 1.5-second intervals; 2) discontinuous pseudoperiodic discharges (DPD), consisting of runs of pseudoperiodic discharges (PD)(phase A) cyclically replaced at about 1-minute intervals with semi-rhythmic theta-delta activities (phase B); 3) non-rapid eye movement (NREM) sleep-like pattern, with dominant 0.5- to 4-Hz activities, less rhythmic than the EEG of phase B. Only these three EEG patterns occurred spontaneously during the repeated polygraphic sessions. The NREM sleep-like pattern was found only in the first recording, whereas the following polygraphic sessions were occupied exclusively by SPD or by a DPD pattern. SPD was associated with either a relatively high level of vigilance (along the first three recordings) or a state of alert-appearing silent immobility (following the fourth recording). During DPD, the patient was unable to accomplish any voluntary movement and fluctuated between levels of greater arousal (phase A) and lesser arousal (phase B). Just as in stage 2 coma, the fluctuations between phases A and B of DPD were synchronous with phasic modifications of muscle activity and neurovegetative functions. In particular, reinforcement of muscle tone and myoclonic spasms coincided with phase A, whereas heart rate deceleration and respiratory pauses or decrease in flow were synchronous with phase B. As EEG evolved toward the disappearance of DPD and finally to flatness, the phase-locked coordination among arousal, somatic and vegetative activities was progressively impaired and was replaced with an uncontrolled exaggeration of cardiorespiratory activity. The genetic, neuropathological and polysomnographic differences between CJD and another prion disease, fatal familial insomnia, are discussed.
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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↗
Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein.
Prion-related encephalopathies are characterized by cerebral accumulation of a post-translationally modified form of the cellular prion protein (PrPC), designated PrPSc. Evidence suggests that the conversion from PrPC to PrPSc involves changes in the secondary structure leading to an increase in beta-sheet content. We have previously shown that a synthetic peptide homologous to residues 106-126 of human PrP, belonging to a predicted alpha-helical domain, exhibits a beta-sheet conformation, forms amyloid-like fibrils, and is neurotoxic in vitro. The present study investigated how different chemicophysical conditions such as pH and ionic strength or a membrane-like environment influenced the secondary structure of this peptide. PrP 106-126 exhibited a predominantly beta-sheet structure in 200 mM phosphate buffer, pH 5.0, but a combination of beta-sheet and random coil structure in 200 mM phosphate buffer, pH 7.0, or in deionized water. The addition of trifluoroethanol (50% final concentration) to solutions of peptide in deionized water induced the appearance of an alpha-helical secondary structure, but did not modify the beta-sheet conformation of the peptide dissolved in 200 mM phosphate buffer, pH 5.0. In the presence of micelles formed by a 5% solution of sodium dodecyl sulfate, PrP 106-126 showed a high content of alpha-helix. When the peptide was dissolved in 5 mM phosphate buffer, pH 7.4, and incubated with liposomes, it changed from a prevalently random coil structure to a beta-sheet conformation. The environment-dependent conformational polymorphism of PrP 106-126 and its marked tendency to form stable beta-sheet structures at acidic pH could account for the shift from alpha-helix to beta-sheet associated with the conversion of PrPC to PrPSc, which occurs most likely in the endosomal-lysosomal compartment.
Amino Acid Sequence↗
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.
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Cerebrospinal fluid levels of amyloid beta-protein precursor are low in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.
We studied levels of amyloid beta-protein precursor (beta PP) in CSF from four patients affected with Gerstmann-Sträussler-Scheinker disease and one asymptomatic gene-carrier from an Indiana kindred. Levels of beta PP were decreased in all affected patients with the lowest levels occurring in the clinically most severely affected patients. Correlation of neuropathology with CSF data in three patients suggested that low beta PP in CSF may be associated with beta PP accumulation in neurites surrounding cortical and cerebellar amyloid deposits.
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Synthetic peptides homologous to prion protein residues 106-147 form amyloid-like fibrils in vitro.
Gerstmann-Sträussler-Scheinker disease (GSS) is a prion-related encephalopathy pathologically characterized by massive deposition of prion protein (PrP) amyloid in the central nervous system. The major component of amyloid fibrils isolated from patients of the Indiana kindred of GSS (GSS-Ik) is an 11-kDa fragment of PrP spanning residues 58 to approximately 150. These patients carry a missense mutation of the PRNP gene, causing a Phe-->Ser substitution at codon 198. We investigated fibrillogenesis in vitro by using synthetic peptides homologous to consecutive segments of GSS-Ik amyloid protein (residues 57-64, 89-106, 106-126, and 127-147) as well as peptides from the PrP region with the GSS-Ik mutation (residues 191-205 and 181-205, both wild type and mutant). Peptide PrP-(106-126) formed straight fibrils similar to those extracted from GSS brains, whereas peptide PrP-(127-147) formed twisted fibrils resembling scrapie-associated fibrils isolated from subjects with transmissible spongiform encephalopathies. Congo red staining and x-ray fibril diffraction showed that both straight and twisted fibrils had tinctorial and conformational properties of native amyloid. Conversely, the other peptides did not form amyloid-like fibrils under similar conditions. These findings suggest that the sequence spanning residues 106-147 of PrP is central to amyloid fibril formation in GSS and related encephalopathies.
Amino Acid Sequence↗
Molecular characteristics of a protease-resistant, amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein.
In the prion-related encephalopathies the prion protein is converted to an altered form, known as PrPSc, that is partially resistant to protease digestion. This abnormal isoform accumulates in the brain and its protease-resistant core aggregates extracellularly into amyloid fibrils. We have investigated the conformational properties, aggregation behaviour and sensitivity to protease digestion of a synthetic peptide homologous to residues 106-126 of human PrP, which was previously found to form amyloid-like fibrils in vitro and displayed neurotoxic activity toward primary cultures of rat hippocampal neurons. A scrambled sequence of peptide PrP 106-126 was used as a control. By circular dichroism, PrP 106-126 exhibited a secondary structure composed largely of beta-sheet, whereas the scrambled sequence of PrP 106-126 showed a random coil structure. The beta-sheet content of PrP 106-126 was much higher in 200 mM phosphate buffer at pH 5.0 than in the same buffer at pH 7.0. Laser light scattering analysis showed that PrP 106-126 aggregated immediately after dissolution in 20 mM or 200 mM phosphate buffer, pH 5.0 and 7.0, whereas scrambled PrP 106-126 did not. PrP 106-126 aggregates had an average hydrodinamic diameter of 100 nm and an average molecular weight of 12 x 10(6) +/- 30% Daltons, corresponding to the aggregation of 6000 +/- 30% molecules. Peptide PrP 106-126 showed partial resistance to digestion with Proteinase K and Pronase, whereas scrambled PrP 106-126 was completely degraded by incubation with the enzymes at 37 degrees C for 30 minutes.
Amino Acid Sequence↗
A68 is a component of paired helical filaments of Gerstmann-Sträussler-Scheinker disease, Indiana kindred.
Gerstmann-Sträussler-Scheinker disease in the Indiana kindred is pathologically characterized by prion protein amyloid deposits and neurofibrillary tangles (NFT) with paired helical filaments (PHF). Using antibodies to various domains of the tau molecule, we investigated the composition of PHF in this family by immunocytochemistry and immunoblot analysis. The results indicate that A68 is a component of NFT in this family as it is in Alzheimer's disease, and suggest that post-translational modifications of tau leading to formation of A68 are not unique to Alzheimer's disease.
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Neurotoxicity of a prion protein fragment.
The cellular prion protein (PrPC) is a sialoglycoprotein of M(r) 33-35K that is expressed predominantly in neurons. In transmissible and genetic neurodegenerative disorders such as scrapie of sheep, spongiform encephalopathy of cattle and Creutzfeldt-Jakob or Gerstmann-Sträussler-Scheinker diseases of humans, PrPC is converted into an altered form (termed PrPSc) which is distinguishable from its normal homologue by its relative resistance to protease digestion. PrPSc accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates extracellularly into amyloid fibrils. The process is accompanied by nerve cell loss, whose pathogenesis and molecular basis are not understood. We report here that neuronal death results from chronic exposure of primary rat hippocampal cultures to micromolar concentrations of a peptide corresponding to residues 106-126 of the amino-acid sequence deduced from human PrP complementary DNA. DNA fragmentation of degenerating neurons indicates that cell death occurred by apoptosis. The PrP peptide 106-126 has a high intrinsic ability to polymerize into amyloid-like fibrils in vitro. These findings indicate that cerebral accumulation of PrPSc and its degradation products may play a role in the nerve cell degeneration that occurs in prion-related encephalopathies.
Amino Acid Sequence↗
Ubiquitinated neurites are associated with preamyloid and cerebral amyloid beta deposits in patients with hereditary cerebral hemorrhage with amyloidosis Dutch type.
Hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D) is characterized clinically by recurrent strokes and pathologically by deposition of amyloid beta (A beta) in cerebral vessel walls and, to a lesser extent, in the neuropil. Distinct from Alzheimer's disease, amyloid formation in HCHWA-D is not associated with neurofibrillary changes. Since a central issue in the pathophysiology of Alzheimer's disease and related conditions is the role of A beta in the neurodegenerative process, we investigated HCHWA-D brains for the presence of neuritic abnormalities using antibodies to ubiquitin and to phosphorylated neurofilaments. The study showed that amyloid deposits in the vessel walls and in the neuropil were surrounded by abnormal ubiquitinated neurites, suggesting that A beta deposition induces neuritic changes.
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Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35.
To investigate whether and how amyloid-beta protein (A beta) is involved in the neurodegenerative changes characteristic of Alzheimer's disease (AD), primary hippocampal neurones from foetal rat brain were exposed acutely and chronically to micromolar concentrations of a synthetic peptide homologous to residues 25-35 of A beta (beta 25-35). A single application of this peptide (25-100 microM) was ineffective but when the neuronal cultures were exposed to beta 25-35 (25-100 microM) repeatedly every two days for ten days, cell survival was dramatically reduced. The structural changes and the DNA fragmentation of cells chronically exposed to the peptide suggested that neuronal death occurred by apoptosis. Furthermore, beta 25-35 showed the intrinsic ability to polymerize into amyloid-like fibrils in vitro. These results confirm the potential pathogenic role of A beta in AD, and indicate that amyloid fibrils may induce neuronal death through a specific programmed process.
Amino Acid Sequence↗
Beta PP participates in PrP-amyloid plaques of Gerstmann-Sträussler-Scheinker disease, Indiana kindred.
Gerstmann-Sträussler-Scheinker disease in the Indiana kindred is pathologically characterized by deposits of PrP-amyloid, neurofibrillary tangles and degenerating neurites. The aim of this study was to investigate seven patients of different ages for beta PP and A beta immunoreactivities associated with PrP-amyloid deposits and degenerating neurites. In one asymptomatic individual with PrP-amyloid deposits, Alz50 and A beta immunoreactivities were absent. In six symptomatic patients, the degenerating neurites surrounding PrP-amyloid deposits were labeled by Alz50 and by antibodies to synaptophysin, ubiquitin and the N- and C-terminal domains of beta PP. In one symptomatic, senile patient, A beta immunoreactivity was present in the extracellular space, often in association with PrP-amyloid deposits. The analysis of the immunohistochemical findings suggested that in the Indiana kindred the intracellular accumulation of beta PP, synaptophysin and ubiquitinated material most probably revealed a reaction of neurites to PrP-amyloid, whereas the extracellular deposition of A beta was likely an age-related phenomenon.
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Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.
Gerstmann-Sträussler-Scheinker disease (GSS) is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. In GSS, the amyloid is immunoreactive to antisera raised against the prion protein (PrP) 27-30, a proteinase K-resistant peptide of 27-30 kDa that is derived by limited proteolysis from an abnormal isoform of a neuronal sialoglycoprotein of 33-35 kDa designated PrPSc. Polyclonal antibodies raised against synthetic peptides homologous to residues 15-40 (P2), 90-102 (P1), and 220-232 (P3) of the amino acid sequence deduced from hamster PrP cDNA were used to investigate immunohistochemically the distribution of PrP and PrP fragments in the brains of two patients from the Indiana kindred of GSS. Two types of anti-PrP-immunoreactive deposits were found: (i) amyloid deposits, which were exclusively labeled by anti-P1 antiserum to residues 90-102 of PrP, and (ii) preamyloid deposits, which were labeled by all anti-PrP antisera but did not exhibit the tinctorial and optical properties of amyloid. The latter appeared as diffuse immunostaining of the neuropil that targeted to areas in which amyloid deposits were most abundant. They were partially resistant to proteinase K digestion and consisted ultrastructurally of amorphous, flaky, electron-dense material. These findings substantiate our previous observation that the major amyloid component in the GSS Indiana kindred is an internal fragment of PrP and indicate that full-length abnormal isoforms of PrP and/or large PrP fragments accumulate in brain regions most affected by amyloid deposition. These findings support the view that in the GSS Indiana kindred a stepwise degradation of PrP occurs in situ in the process of amyloid fibril formation.
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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↗
Down syndrome as a key to the time sequence of brain changes in Alzheimer disease.
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Alzheimer Disease↗
Relationship between non-fibrillary amyloid precursors and cell processes in the cortical neuropil of Alzheimer patients.
We examined the ultrastructural localization of amyloid beta-protein in 8 Alzheimer neocortical biopsies. Intense immunoreactivity was located extracellularly on amyloid fibrils and amorphous material. Amorphous labelled material was also found in cell processes. No ultrastructural cell marker, such as glial fibrils, glycogen, tubules, paired helical filaments (PFHs) or synaptic vesicles could be seen in these processes that could allow their identification as glial processes, neurites or presynaptic terminals, respectively; occasional membrane stacks were observed. These findings suggest that preamyloid deposits are related to cell processes and, by elimination, that postsynaptic terminals may be involved in abnormal metabolism of the amyloid fibril precursors.
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Alzheimer patients: preamyloid deposits are immunoreactive with antibodies to extracellular domains of the amyloid precursor protein.
In patients with Alzheimer's disease, in patients with Down's syndrome and in aged non-demented individuals, anti-beta-protein antibodies label not only the fibrillary amyloid, but also preamyloid deposits. The latter are made up of amorphous material lacking the tinctorial, optical and ultrastructural properties of amyloid fibrils. To investigate the antigenic profile of preamyloid deposits, we have carried out an immunohistochemical study on specimens of cerebral cortex from 4 Alzheimer patients and two non-demented individuals, using antibodies to the beta-protein (anti-SP28), the C-terminal region of the amyloid precursor protein (APP) (anti-SP20) and an APP extracellular epitope between residues 50 and 100 (anti-preA4). Anti-preA4 and anti-SP28 immunoreactivity was found to be present in preamyloid deposits, whereas anti-SP20 immunoreactivity was not. These findings suggest that an extracellular portion of APP, close to the N-terminus of the molecule, participates with beta-protein in the composition of preamyloid deposits.
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