T-type Ca channel enhancer SAK3 administration improves the BPSD-like behaviors in App knock-in mice.

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.