| First Author | Schnöder L | Year | 2023 |
| Journal | FASEB J | Volume | 37 |
| Issue | 2 | Pages | e22778 |
| PubMed ID | 36688823 | Mgi Jnum | J:338758 |
| Mgi Id | MGI:7514434 | Doi | 10.1096/fj.202201512R |
| Citation | Schnoder L, et al. (2023) Deficiency of IKKbeta in neurons ameliorates Alzheimer's disease pathology in APP- and tau-transgenic mice. FASEB J 37(2):e22778 |
| abstractText | In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-beta-peptide (Abeta) 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 IKKbeta specifically in neurons, and observed that IKKbeta deficiency reduced cerebral Abeta and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKbeta 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, IKKbeta deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKbeta 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 IKKbeta in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKbeta deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Abeta production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKbeta deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Abeta and p-tau, before IKKbeta/NF-kappaB can be targeted for AD therapies. |
