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Ruben Vidal

Publications and source records attributed to Ruben Vidal.

8 recordsLinked to original sources
PubMed2005

Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques.

Cotton wool plaques (CWPs) are round lesions that lack a central amyloid core. CWPs have been observed in individuals affected by early-onset familial Alzheimer disease (FAD) associated with mutations in the presenilin 1 (PSEN1) gene. Here we present the characterization of the amyloid-beta (Abeta) peptides deposited in the brain of an individual affected by FAD carrying the novel missense (V261I) mutation in the PSEN1 gene. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to determine the Abeta peptide species present in the cerebral and cerebellar cortices, in leptomeningeal vessels, and in CWPs isolated by laser microdissection (LMD). Our results indicate that amino-terminally truncated Abeta peptide species ending at residues 42 and 43 are the main Abeta peptides deposited in brain parenchyma and LMD-CWPs in association with the PSEN1 V261I mutation. Full-length Abeta1-42 and Abeta1-43 peptide species were underrepresented. CWPs were not found to be associated with vessels and did not contain Abeta1-40 peptides, the main component of the vascular deposits. Although Abeta deposits were present mostly in the form of CWPs in the cerebral cortex and as diffuse deposits in the cerebellar cortex, a similar array of amino-terminally truncated Abeta peptide species was seen in both cases. The biochemical data support the concept that parenchymal and vascular amyloid deposits are associated with a different array of Abeta peptide species. The generation and parenchymal deposition of highly insoluble amino-terminally truncated Abeta peptides may play an important role in the pathogenesis of AD and must be taken into consideration in developing new diagnostic and therapeutic strategies.

Alzheimer Disease↗
PubMed2004

Immunolocalization of the oligodendrocyte transcription factor 1 (Olig1) in brain tumors.

Recent in situ hybridization studies showed that mRNA levels of OLIG1 and OLIG2 transcription factors are elevated in oligodendrogliomas. We raised polyclonal antibodies against a synthetic peptide homologous to the human transcription factor Olig1 and studied by immunohistochemistry the expression of Olig1 in 84 brain tumors and in non-neoplastic brain tissues. All oligodendrogliomas, oligoastrocytomas, and dysembryoplastic neuroepithelial tumors showed moderate to strong intranuclear immunoreactivity in cells morphologically identified as oligodendrocytes. In addition, some astrocytomas showed a slight to moderate intranuclear immunoreactivity. None of the other neuroepithelial and non-neuroepithelial tumors showed nuclear immunoreactivity. Double immunostaining of oligodendrogliomas, oligoastrocytomas, and glioblastoma multiforme (GBM) using antibodies against Olig1 and GFAP showed the presence of 3 different cell populations: 1) immunopositive for Olig1 and immunonegative for GFAP, histologically identified as oligodendrocytes; 2) immunopositive only for GFAP, histologically identified as astrocytes; and 3) immunonegative for both antibodies ("null cells"), histologically observed as a population of cells usually with round nuclei and a small amount of cytoplasm. The use of double immunostaining facilitated the distinction among these 3 different tumors. In summary, the use of immunohistochemistry using Olig1 antibodies alone or in combination with anti-GFAP antibody, which can be performed in the routine diagnostic setting, may help in the diagnosis of neuroepithelial tumors.

Adolescent↗
PubMed2004

Neurodegeneration caused by proteins with an aberrant carboxyl-terminus.

In recent years, 2 groups of hereditary neurodegenerative diseases have been recognized in which different genetic defects lead to the accumulation of proteins that contain a carboxyl-terminus that is abnormal in length and primary sequence. In this paper, we review the current knowledge on the molecular basis of diseases from these 2 groups. The first group includes familial British and Danish dementias, in which the molecular genetic defect resides in the BRI2 gene located on chromosome 13. In this group, carboxyl-terminal proteolytic products of the mutant BRI2 proteins aggregate in the extracellular space of the brain and in blood vessels. The second group includes 2 recently described ferritinopathies, in which the molecular genetic defect resides in the ferritin light polypeptide gene located on chromosome 19. In this group, full-length ferritin polypeptides aggregate intracellularly. The study of these conditions has led to the discovery of the BRI2 gene and to the finding of an unsuspected role for ferritin in neurodegeneration. These diseases provide new models in which to study the relationship between abnormal protein aggregation, neuronal cell death, and dementia.

Amino Acid Sequence↗
PubMed2004

Early-onset dementia with Lewy bodies.

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.

Adolescent↗
PubMed2003

Axonal transport of British and Danish amyloid peptides via secretory vesicles.

The ABri and ADan amyloid peptides deposited in familial British and Danish neurodegenerative disorders are generated by processing mutant forms of the precursor protein BRI2. Although the pathogenic process that leads to deposition of amyloid in the brains of patients has been studied extensively, the cellular processes and normal function of the precursor protein did not receive much attention. We observed in a variety of transfected cell lines the presence of two independent proteolytic processing events. In addition to the previously described cleavage, which results in the production of carboxyl-terminal approximately 3 kDa wild-type peptide or approximately 4 kDa ABri or ADan peptides, we describe a novel amino-terminal cleavage site within BRI2. Both cleavages occur within the cis- or medial-Golgi. Following cleavage, the BRI2-derived carboxyl-terminal peptides are transported via a regulated secretory pathway into secretory vesicles in neuronal cells. Worth noting is that expression of wild-type British or Danish mutants of BRI2, in mouse neuroblastoma N2a cells that do not express endogenous BRI2, induces elongation of neurites, which suggests a role for this protein in differentiation of neuronal cells.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The human amyloid-beta precursor protein770 mutation V717F generates peptides longer than amyloid-beta-(40-42) and flocculent amyloid aggregates.

One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-beta precursor protein (AbetaPP) substitution mutation V717F. This mutation is relevant to AD research, since it has been utilized to generate transgenic mice models to study AD pathology and therapeutic interventions. Amyloid beta (Abeta) peptides were obtained from the cerebral tissue of three familial AD subjects carrying the AbetaPP V717F mutation. A combination of ultracentrifugation, size-exclusion, and reverse-phase high performance liquid chromatography, tryptic and cyanogen bromide hydrolysis, amino acid analysis, and matrix-assisted laser desorption ionization and surface-enhanced laser desorption ionization mass spectrometry was used to characterize the familial AD mutant Abeta peptides. The AbetaPP V717F mutation, located 4-6 residues beyond the wild-type AbetaPP gamma-secretase cleavage site, yielded longer Abeta peptides with C termini between residues 43 and 54. In the cerebral cortex these peptides aggregated into thin water- and SDS-insoluble amyloid bundles that condensed into flocculent spherical plaques. In the leptomeningeal arteries the amyloid was deposited in moderate amounts and was primarily composed of the shorter and more soluble Abeta species ending at residues 40, 42, and 44. The single V717F mutation in AbetaPP results in distinctive and drastic changes in the length and tertiary structure of Abeta peptides, which appear to be responsible for the earlier clinical manifestations of dementia and death of these patients.

Amino Acids↗
PubMed2002

Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta.

Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation.

Adult↗