NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production.
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.
Valerio
Alessandra
A
Division of Pharmacology, Department of Biomedical Sciences & Biotechnologies, University of Brescia, Italy. alessandra.valerio@unimi.it
Boroni
Flora
F
Benarese
Marina
M
Sarnico
Ilenia
I
Ghisi
Valentina
V
Bresciani
Laura Grazia
LG
Ferrario
Marina
M
Borsani
Giuseppe
G
Spano
PierFranco
P
Pizzi
Marina
M
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000633:toxicity; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D051996:Transcription Factor RelA; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)