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Maria Luisa Moro,
Giorgio Giaccone,
Raffaella Lombardi,
Antonio Indaco, Andrea Uggetti,
Michela Morbin,
Stefania Saccucci,
Giuseppe Di Fede,
Marcella Catania,
Dominic M Walsh,
Andrea Demarchi,
Annemieke Rozemuller,
Nenad Bogdanovic,
Orso Bugiani,
Bernardino Ghetti,
Fabrizio Tagliavini
Acta Neuropathologica 03/2013; 125(3):467. · 9.32 Impact Factor
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Maria Luisa Moro,
Giorgio Giaccone,
Raffaella Lombardi,
Antonio Indaco, Andrea Uggetti,
Michela Morbin,
Stefania Saccucci,
Giuseppe Di Fede,
Marcella Catania,
Dominic M Walsh,
Andrea Demarchi,
Annemieke Rozemuller,
Nenad Bogdanovic,
Orso Bugiani,
Bernardino Ghetti,
Fabrizio Tagliavini
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ABSTRACT: Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.
Acta Neuropathologica 11/2012; · 9.32 Impact Factor
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ABSTRACT: Bdelloid rotifers survive desiccation and starvation by halting activity and entering a kind of dormancy. To understand the mechanisms of survival in the absence of food source, we studied the anatomical and ultrastructural changes occurring in a bdelloid species, Macrotrachela quadricornifera Milne 1886, after starvation for different periods. The starved rotifers present a progressive reduction of body size accompanied with a consistent reduction of the volume of the stomach syncytium, where lipid inclusions and digestive vacuoles tend to fade with prolonged starvation. Similar reduction occurs in the vitellarium gland, in which yolk granules progressively decrease in number and size. The changes observed in the syncytia of the stomach and the vitellarium suggest that during starvation M. quadricornifera uses resources diverted from the stomach syncytium first and from the vitellarium syncytium later, resources that are normally allocated to reproduction. The fine structure of starved bdelloids is compared with that of anhydrobiotic bdelloids, revealing that survival during either forms of dormancy is sustained by different physiological mechanisms.
Journal of Morphology 01/2012; 273(1):1-7. · 1.54 Impact Factor
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Giacomina Rossi,
Antonio Bastone,
Elena Piccoli,
Giulia Mazzoleni,
Michela Morbin, Andrea Uggetti,
Giorgio Giaccone,
Sarah Sperber,
Marten Beeg,
Mario Salmona,
Fabrizio Tagliavini
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ABSTRACT: Frontotemporal lobar degeneration (FTLD) can be sporadic or familial. The genes encoding the microtubule-associated protein tau (MAPT) and progranulin (GRN) are the most relevant genes so far known causing the hereditary forms. Following genetic screening of patients affected by FTLD, we identified 2 new MAPT mutations, P364S and G366R, the former in a sporadic case. In the study we report the clinical and genetic features of the patients carrying these mutations, and the functional effects of the mutations, analyzed in vitro in order to investigate their pathogenic character. Both mutations resulted in reduced ability of tau to promote microtubule polymerization; the P364S protein variant also showed a high propensity to aggregate into filaments. These results suggest a high probability that these mutations are pathogenic. Our findings highlight the importance of genetic analysis also in sporadic forms of FTLD, and the role of in vitro studies to evaluate the pathologic features of new mutations.
Neurobiology of aging 09/2011; 33(4):834.e1-6. · 5.94 Impact Factor
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Giorgio Giaccone,
Michela Morbin,
Fabio Moda,
Mario Botta,
Giulia Mazzoleni, Andrea Uggetti,
Marcella Catania,
Maria Luisa Moro,
Veronica Redaelli,
Alberto Spagnoli,
Roberta Simona Rossi,
Mario Salmona,
Giuseppe Di Fede,
Fabrizio Tagliavini
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ABSTRACT: Mutations of three different genes, encoding β-amyloid precursor protein (APP), presenilin 1 and presenilin 2 are associated with familial Alzheimer's disease (AD). Recently, the APP mutation A673V has been identified that stands out from all the genetic defects previously reported in these three genes, since it causes the disease only in the homozygous state (Di Fede et al. in Science 323:1473-1477, 2009). We here provide the detailed neuropathological picture of the proband of this family, who was homozygous for the APP A673V mutation and recently came to death. The brain has been studied by histological and immunohistochemical techniques, at the optical and ultrastructural levels. Cerebral Aβ accumulation and tau pathology were severe and extensive. Peculiar features were the configuration of the Aβ deposits that were of large size, mostly perivascular and exhibited a close correspondence between the pattern elicited by amyloid stainings and the labeling obtained with immunoreagents specific for Aβ40 or Aβ42. Moreover, Aβ deposition spared the neostriatum while deeply affecting the cerebellum, and therefore was not in compliance with the hierarchical topographical sequence of involvement documented in sporadic AD. Therefore, the neuropathological picture of familial AD caused by the APP recessive mutation A673V presents distinctive characteristics compared to sporadic AD or familial AD inherited as a dominant trait. Main peculiar features are the morphology, structural properties and composition of the Aβ deposits as well as their topographic distribution in the brain.
Acta Neuropathologica 12/2010; 120(6):803-12. · 9.32 Impact Factor
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ABSTRACT: Bdelloid rotifers are aquatic microinvertebrates able to cope with the loss of environmental water by entering dormancy, and are thus capable of living in temporary habitats. When water is evaporating, bdelloids contract into "tuns", silence metabolism and lose water from the body, a condition known as anhydrobiosis. Under controlled conditions, a bdelloid species (Macrotrachela quadricornifera) was made anhydrobiotic, and its morphology was studied by light, confocal and electron microscopy. A compact anatomy characterizes the anhydrobiotic rotifer, resulting in a considerable reduction of its body volume: the internal organs, precisely packed together, occupy the body cavity almost completely and the lumen of hollow organs disappears. Remarkable ultrastructural changes characterize the anhydrobiotic condition. The mitochondria are wholly surrounded by a ring of electron-dense particles, and the epidermal pores, open in the hydrated specimens, become gradually closed by structures similar to epithelial junctions. The cilia are densely packed: microtubules are still identifiable, but the axonemal organization appears disrupted. This is the first extensive comparative study on the morphological changes associated with the anhydrobiosis process in a rotifer, providing the basis for an improved understanding of the processes involved in this extreme adaptation.
Journal of Structural Biology 04/2010; 171(1):11-7. · 3.41 Impact Factor
