Alzheimer's disease (AD) is the most common neurodegenerative disorder. There are only a few therapeutic strategies for AD. Therefore, it is important to find more effective therapeutic agents. Low aggregated form of amyloid-β (Aβ oligomer) is known as a primary cause of AD. Previous studies showed that intracerebroventricular (i.c.v.) injection of synthetic Aβ oligomer induces AD-like cognitive dysfunction. In this study, we explored whether the Aβ oligomer-induced memory deficit is improved by β-hydroxybutyrate, a ketone body used as an energetic substrate in the brain.
We used a novel object recognition task for cognitive assessment. As reported previously, i.c.v. injection of Aβ oligomer (1 μM) impaired memory acquisition. We found that intraperitoneal (i.p.) injection of β-hydroxybutyrate (600 mg/kg) recovered the memory impairment induced by Aβ oligomer. A recent study revealed that β-hydroxybutyrate is not only an energetic substrate but also an endogenous and specific inhibitor of class1 histone deacetylases (HDACs). Therefore we examined effects of a HDAC inhibitor trichostatin A (TSA) on the Aβ oligomer-induced memory impairment. Although Aβ oligomer impaired memory acquisition, i.p. injection of TSA (2 mg/kg) recovered the memory impairment. These results show that β-hydroxybutyrate, which has two properties of energetic substrates and HDAC inhibitors, improves cognitive dysfunction induced by Aβ oligomer, and also suggest that β-hydroxybutyrate as HDAC inhibitors is important to improve memory impairment.