T-type Ca2+ channel enhancer SAK3 administration improves the BPSD-like behaviors in AppNL-G-F/NL-G-F knock-in mice

Abstract Alzheimer’s disease (AD) accounts for the majority of dementia among the elderly. In addition to cognitive impairment, behavioral and psychological symptoms (BPSD) such as depression tendency and increased aggression impose a great burden on the patient. However, there is still no rational therapeutic drug for BPSD. Recently, we developed a novel AD therapeutic candidate, SAK3, and demonstrated that it improved cognitive dysfunction in AppNL-G-F/NL-G-F knock-in (NL-G-F) mice. In this study, we investigated whether acute SAK3 administration improved BPSD in addition to cognitive improvement. Acute SAK3 administration improved BPSD, including anxiolytic and depressive-like behaviors, and ameliorated aggressive behaviors. Furthermore, continuous SAK3 administration improved anxiolytic and depressive-like behaviors. Intriguingly, the anti-anxiolytic and cognitive improvement lasted two weeks after the withdrawal of SAK3, whereas the anti-depressive action did not. Taken together, SAK3 had comprehensive beneficial effects on BPSD behavior.