Deficiency of IKK in neurons ameliorates Alzheimer's disease pathology in APP- and tau-transgenic mice

In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-beta-peptide (A beta) 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 IKK beta specifically in neurons, and observed that IKK beta deficiency reduced cerebral A beta and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKK beta 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, IKK beta deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKK beta 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 IKK beta in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKK beta deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing A beta production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKK beta deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between A beta and p-tau, before IKK beta/NF-kappa B can be targeted for AD therapies.