Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease
Autore:
Glabe, C;
Indirizzi:
Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA Univ Calif Irvine Irvine CA USA 92697 iol & Biochem, Irvine, CA 92697 USA
Titolo Testata:
JOURNAL OF MOLECULAR NEUROSCIENCE
fascicolo: 2, volume: 17, anno: 2001,
pagine: 137 - 145
SICI:
0895-8696(200110)17:2<137:IMOAAA>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
BETA-PROTEIN-PRECURSOR; SENILE PLAQUES; DYSTROPHIC NEURITES; HEPARAN-SULFATE; ULTRASTRUCTURAL-LOCALIZATION; END-PRODUCTS; NEUROFIBRILLARY TANGLES; MUTANT PRESENILINS; FREE-RADICALS; CORE PROTEIN;
Keywords:
intracellular amyloid A beta; dense bodies dystrophic neurites; amyloid accumulation; Alzheimer's pathogenesis; lysosomes;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
92
Recensione:
Indirizzi per estratti:
Indirizzo: Glabe, C Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA Univ Calif Irvine Irvine CA USA 92697 chem, Irvine, CA 92697 USA
Citazione:
C. Glabe, "Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease", J MOL NEURO, 17(2), 2001, pp. 137-145

Abstract

Cell-culture studies have revealed some of the fundamental features of theinteraction of amyloid A beta with cells and the mechanism of amyloid accumulation and pathogenesis in vitro. A beta1-42, the longer isoform of amyloid that is preferentially concentrated in senile plaque (SP) amyloid deposits in Alzheimer's disease (AD), is resistant to degradation and accumulatesas insoluble aggregates in late endosomes or lysosomes. Once these aggregates have nucleated inside the cell, they grow by the addition of aberrantlyfolded APP and amyloid-genic fragments of APP, that would otherwise be degraded, onto the amyloid lattice in a fashion analogous to prion replication. This accumulation of heterogeneous aggregated APP fragments and A beta appears to mimic the pathophysiology of dystrophic neurites, where the same spectrum of components has been identified by immunohistochemistry. In the brain, this residue appears to be released into the extracellular space, possibly by a partially apoptotic mechanism that is restricted to the distal compartments of the neuron. Ultimately, this insoluble residue may be further digested to the protease-resistant A betan-42 core, perhaps by microglia,where it accumulates as senile plaques. Thus, the dystrophic neurites are likely to be the source of the immediate precursors of amyloid in the senile plaques. This is the opposite of the commonly held view that extracellular accumulation of amyloid induces dystrophic neurites. Many of the key pathological events of AD may also be directly related to the intracellular accumulation of this insoluble amyloid. The aggregated, intracellular amyloid induces the production of reactive oxygen species (ROS) and lipid peroxidation products and ultimately results in the leakage of the lysosomal membrane. The breakdown of the lysosomal membrane may be a key pathogenic event, leading to the release of heparan sulfate and lysosomalhydrolases into the cytosol. Together, these observations provide the novel view that amyloid deposits and some of the early events of amyloid pathogenesis initiate randomly within single cells in AD. This pathogenic mechanism can explain some of the more enigmatic features of Alzheimer's pathogenesis, like the focal nature of amyloid plaques, the relationship between amyloid, dystrophic neurites and neurofibrillary-tangle pathology, and the miscompartmentalization of extracellular and cytosolic components observed in AD brain.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/03/20 alle ore 23:30:47