Deficiency of IKKβ in neurons ameliorates Alzheimer’s disease pathology in APP- and tau-transgenic mice

Abstract Background: Alzheimer’s disease (AD) is pathologically characterized by extracellular deposition of amyloid β peptide (Aβ), intracellular neurofibrillary tangles (composed mainly of phosphorylated tau [p-tau]) and neuroinflammation. The pathogenic role of inflammatory activation in AD has been extensively studied; however, the underlying mechanisms remain unclear. In this project, we investigated how neuronal IKKβ/NF-kB regulates AD-associated pathologies in APP- and tau-transgenic AD mice. Methods: APP- and tau-transgenic mice were cross-bred with ikbkb-floxed and nex-cre knock-in mice to generate AD models with deletion of IKKβ specifically in neurons. After assessing cognitive function with the Morris water maze test, mice were analyzed for Aβ and p-tau levels, microglial numbers, transcription of inflammatory genes, apoptosis and synaptic protein levels in the brain by histological, biochemical and molecular biology methods. To explore pathogenic mechanisms, we analyzed the activity and/or protein levels of: 1) β- and γ-secretases, 2) tau-phosphorylating (e.g., GSK3β and p38α-MAPK) and dephosphorylating enzymes (e.g., PP2A and PP2B), and 3) autophagy-related proteins (e.g., LC3B, beclin1 and SQSTM1/p62). In addition, IKKβ-knockdown and wild-type SH-SY5Y cell lines were created to verify the in vivo results.Results: In APP-transgenic mice, neuronal deficiency of IKKβ decreased Aβ load, inflammatory activation, and apoptosis in the brain, and improved cognitive function and maintenance of synaptic proteins (e.g., PSD-95). IKKβ deficiency decreased BACE1 activity and protein in the brain and cultured neuronal cells. In tau-transgenic mice, neuronal deficiency of IKKβ decreased p-tau, shifted pro- to anti-inflammatory activation and inhibited autophagy in the brain. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau. However, deficiency of IKKβ in neurons did not alter the cognitive function and even increased apoptosis in the brain.Conclusions: Deficiency of IKKβ in neurons attenuates Aβ and p-tau loads in the brains of AD mice. As possible molecular mechanisms, IKKβ deficiency decreases BACE1 activity, thereby reducing Aβ production, and increases PP2A expression, promoting p-tau dephosphorylation. However, IKKβ deficiency protects neurons only in APP-transgenic mice, but not in tau-transgenic AD mice. Further studies are needed before IKKβ/NF-kB can be targeted for AD therapies.

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