NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production
Articolo
Data di Pubblicazione:
2006
Citazione:
NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production / A. Valerio, F. Boroni, M. Benarese, I. Sarnico, V. Ghisi, L.G. Bresciani, M. Ferrario, G. Borsani, P. Spano, M. Pizzi. - In: EUROPEAN JOURNAL OF NEUROSCIENCE. - ISSN 0953-816X. - 23:7(2006 Apr), pp. 1711-1720. [10.1111/j.1460-9568.2006.04722.x]
Abstract:
Beta-amyloid (Abeta) peptides are key proteins in the pathophysiology of
Alzheimer's disease (AD). While Abeta42 aggregates very rapidly to form early
diffuse plaques, supplemental Abeta40 deposition is required to form mature
neuritic plaques. We here investigated the role of nuclear factor-kappaB
(NF-kappaB) pathway in Abeta40-mediated neuronal damage and amyloid pathology.
In rat primary neurons and human postmitotic neuronal cells, the Abeta peptide
induced a dose-dependent neuronal death, reduced the levels of the
anti-apoptotic protein Bcl-XL, enhanced the cytosolic release of cytochrome c,
and elicited the intracellular accumulation and secretion of Abeta42 oligomers.
Moreover, Abeta40 activated the NF-kappaB pathway by selectively inducing the
nuclear translocation of p65 and p50 subunits, and promoted an apoptotic profile
of gene expression. As inhibitors of the NF-kappaB pathway, we tested the
capability of a double-stranded kappaB decoy oligonucleotide, the
anti-inflammatory drug aspirin and the selective IkappaB kinase 2 inhibitor,
AS602868, to modify the Abeta40-mediated effects. These treatments, transiently
applied before Abeta exposure, completely inhibited p50/p65 nuclear
translocation and neuronal damage. The kappaB decoy also inhibited the
Abeta-induced release of cytochrome c, restored the levels of Bcl-XL, and
prevented intraneuronal accumulation and secretion of Abeta42. These results
open up interesting perspectives on the development of novel strategies
targeting out NF-kappaB p50/p65 dimers for pharmacological intervention in AD
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Alzheimer's disease; Apoptosis; Human; Mouse; Transcription factors
Elenco autori:
A. Valerio, F. Boroni, M. Benarese, I. Sarnico, V. Ghisi, L.G. Bresciani, M. Ferrario, G. Borsani, P. Spano, M. Pizzi
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