Deficiency of IKKβ in neurons ameliorates Alzheimer's disease pathology in APP‐ and tau‐transgenic mice

Abstract

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

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

“…The inhibition of IKKβ (also known as IKK2), with the aim of disrupting the activation of NF-κB, has garnered significant attention in the pursuit of therapies for inflammatory, autoimmune, respiratory, and oncological conditions [40][41][42][43]. In an AD APP-transgenic murine model, IKKβ inhibition proved to be effective in reducing inflammatory microglial activation and decreasing TNF-α, Il-1β, and iNOS inflammatory gene transcription caused by Aβ deposits, thereby improving cognitive functions [44,45]. Currently available small-molecule, anti-AD drugs remain ineffective in terminating disease progression [46]; therefore, the exploration of novel, innovative therapeutic areas is still a major priority.…”

IKKβ inhibits cognitive memory and adult hippocampal neurogenesis via the β-catenin pathway

“…Previous studies have underscored the diverse roles of IKKβ in various cell types, indicating its involvement in essential cellular functions. The absence of neuronal IKKβ is associated with the amelioration of Alzheimer's disease pathology in amyloid precursor protein and tau transgenic mice [12]. Tamoxifen-induced IKKβ knockout and NF-κB inhibition in striatal neurons increase striatal neurodegeneration in mice with Huntington's disease.…”