Deficiency of IKKß in neurons ameliorates Alzheimer's disease pathology in APP- and tau-transgenic mice.
FASEB J
; 37(2): e22778, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36688823
ABSTRACT
In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-ß-peptide (Aß) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKß specifically in neurons, and observed that IKKß deficiency reduced cerebral Aß and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKß decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKß deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKß deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKß in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKß deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aß production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKß deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aß and p-tau, before IKKß/NF-κB can be targeted for AD therapies.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Alzheimer
/
Neuroblastoma
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article