Inhibition of PKA attenuates memory deficits induced by β-amyloid (1–42), and decreases oxidative stress and NF-κB transcription factors

Alzheimer's disease (AD), the most relevant cause of dementia in elderly, is characterized by amyloid β (Aβ) containing plaques and neurofibrillatory tangles, synaptic and neuronal loss, along with progressive cognitive impairment in short-term memory. However, mechanistic links between protein kinase A (PKA), oxidative stress and memory loss in response to Aβ remain elusive. In the present study, we examined the effects of post-training bilateral intra-hippocampal infusions of the specific protein kinase AII inhibitor, H-89, on memory deficits induced by Aβ (1–42) in Aβ-pretreated rats. H-89 and Aβ were administered immediately after completion of training. All animals were trained for 4 consecutive days and tested 9 and 19 days after the infusions. Significant differences were observed in the time and distance of finding the hidden platform in Aβ treated animals after 19 days. Interestingly, intra-hippocampal infusion of H-89 (5 μM/side) significantly prevented the Aβ-induced memory impairment. Furthermore, evaluation of NFκB (nuclear factor-κB), and antioxidant enzymes, such as γ-GCS (glutamylcysteine synthetase), HO-1 (hemeoxygenase-1), GSH (glutathione), and SOD (superoxide dismutase) confirmed the protective effect of H-89. Given the possible neuroprotective effects of H-89 on Aβ-induced memory impairment, our results may open a new avenue for the prevention of AD by PKAII signaling pathway inhibitor.

► The effects of PKA inhibitor H-89 on Aβ-induced memory deficit was studied in rats. ► Spatial memory retention was assessed 9 and 19 days after infusions of H-89 and Aβ. ► Intra-hippocampal infusion of H-89 prevented the Aβ-induced memory impairment. ► NFκB signal transduction pathway is involved in Aβ-induced memory deficit. ► Evaluation of NFκB, γ-GCS, HO-1, GSH and SOD confirmed the protective effect of H-89.