Restoring neuronal excitability and spatial memory through inhibiting amyloid-β-induced hyperactive NF-κB in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder associated with aberrant neuronal activity. In AD, NF-κB, a key transcription factor and inflammatory mediator, becomes hyperactive, influencing gene expression, and likely neuronal excitability. This study investigates whether inhibiting intracortical injection of amyloid-β peptides (Aβ)-induced hyperactive NF-κB can restore spatial memory impairment and abnormal neuronal activity in rats. We observed that intracortical injection of Aβ increases immunoreactivity of phosphorylated-p65 in CA1 pyramidal neurons. We demonstrated that in vivo treatment of rats with JSH-23 restores anxiety-like behaviors as well as spatial learning and memory, as assessed by elevated plus maze and Morris water maze, respectively. In addition, using patch-clamp recording we showed that the intrinsic excitability of CA1 pyramidal neurons, particularly in terms of the evoked spikes, is reduced in Aβ-injected rats along with altered resting membrane properties. Incubating acute brain slices from control rats in aCSF containing JSH-23 did not influence the neuronal activity. In contrast, this incubation restored almost all of the passive- and activity-dependent properties of CA1 pyramidal neurons in brain slices from Aβ-injected rats. Furthermore, we found that Aβ-induced enhancement of Ih currents and after-hyperpolarization amplitude (AHP) are reduced by JSH-23 incubation, possibly underlying rescuing effects of NF-κB inhibition at behavioral and cognitive level. Collectively, our results suggest that hyperactive NF-κB signaling in AD is associated with abnormal neuronal activity and deficits in cognitive functions. Moreover, pharmacologic inhibition of this signaling molecule restores neuronal excitability, as well as rescues spatial memory, likely through influencing Ih currents and AHP.