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Titolo:
Lysosomal membrane damage in soluble A beta-mediated cell death in Alzheimer's disease
Autore:
Ditaranto, K; Tekirian, TL; Yang, AJ;
Indirizzi:
Nathan S Kline Inst Psychiat Res, Dementia Res Program, Orangeburg, NY 10962 USA Nathan S Kline Inst Psychiat Res Orangeburg NY USA 10962 rg, NY 10962 USA Massachusetts Gen Hosp, Genet & Aging Unit, Boston, MA 02114 USA Massachusetts Gen Hosp Boston MA USA 02114 ing Unit, Boston, MA 02114 USA Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA Massachusetts Gen Hosp Boston MA USA 02114 t Neurol, Boston, MA 02114 USA Harvard Univ, Sch Med, Boston, MA 02129 USA Harvard Univ Boston MA USA 02129 vard Univ, Sch Med, Boston, MA 02129 USA
Titolo Testata:
NEUROBIOLOGY OF DISEASE
fascicolo: 1, volume: 8, anno: 2001,
pagine: 19 - 31
SICI:
0969-9961(200102)8:1<19:LMDISA>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
CARBOXYL-TERMINAL DERIVATIVES; AMYLOID PROTEIN-PRECURSOR; NEUROFIBRILLARY TANGLES; ACRIDINE-ORANGE; CULTURED-CELLS; PC12 CELLS; PEPTIDE; BRAIN; AGGREGATION; NEURONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Ditaranto, K Nathan S Kline Inst Psychiat Res, Dementia Res Program, Orangeburg, NY 10962 USA Nathan S Kline Inst Psychiat Res Orangeburg NY USA 10962 USA
Citazione:
K. Ditaranto et al., "Lysosomal membrane damage in soluble A beta-mediated cell death in Alzheimer's disease", NEUROBIOL D, 8(1), 2001, pp. 19-31

Abstract

Our previous studies suggest that a failure to degrade aggregated A beta1-42 in late endosomes or secondary lysosomes is a mechanism that contributesto intracellular accumulation in Alzheimer's disease. In this study, we demonstrate that cultured primary neurons are able to internalize soluble A beta1-42 from the culture medium and accumulate inside the endosomal/lysosomal system. The intracellular A beta1-42 is resistant to protease degradation and stable for at least 48 h within the cultured neurons. Incubation of cultured neurons with a cytotoxic concentration of soluble A beta1-42 invokes the rapid free radical generation within lysosomes and disruption of lysosomal membrane proton gradient which precedes cell death. The loss of lysosomal membrane impermeability is only specific to the A beta1-42 isoform since incubation of cells with high concentrations of A beta1-40 has no effecton lysosomal hydrolase release. To further support the role of lysosomal membrane damage in A beta -mediated cell death, we demonstrate that photodisruption of acridine orange (AO)-loaded lysosomes with intense blue light induces a relatively rapid synchronous lysosomal membrane damage and neuronaldeath similar to that observed as a result of A beta exposure. AO leaks quickly from late endosomes and lysosomes and partially shifts the fluorescence from an orange fluorescence to a diffuse, green cytoplasmic fluorescence. Such AO relocalization is due to an initial disruption of the lysosomal proton gradient, followed by the release of lysosomal hydrolases into the cytoplasmic compartment. Treatment of cells with either the antioxidant n-propyl gallate or lysosomotropic amine (methylamine) partially blocks the release of lysosomal contents suggesting that this AO relocalization is due to lysosomal membrane oxidation. Based on these findings, we propose that the cell death mediated by the soluble A beta may be fundamentally different from the cell loss observed following extracellular A beta deposition. (C) 2001 Academic Press.

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Documento generato il 19/01/20 alle ore 20:13:33