Alzheimer's disease therapeutic candidate SAK3 is an enhancer of T-type calcium channels

Abstract

Low-threshold Ca2+ spikes are mediated by T-type Ca2+ channels, which have electrophysiological properties of fast inactivation and slow deactivation kinetics. A low membrane potential of approximately −60 mV is sufficient to trigger channel opening. We recently introduced a novel T-type Ca2+ channel enhancer that improves cognition and inhibits amyloid beta aggregation in an Alzheimer's disease (AD) mouse model. The enhancer stimulates ACh release, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and neurogenesis in the hippocampus. Then, we discuss how T-type Ca2+ channel enhancer improves cognition and impaired neurogenesis and how CaMKII signaling in neurodegenerative diseases reduces amyloid beta aggregation. We provide a perspective of the potential AD therapies to target CaMKII signaling. In this context, we overview our attempts leading to the development of a T-type Ca2+ channel enhancer as cognitive enhancer, the action of which has been associated with CaMKII and presumably proteasome activity. Keywords: T-type Ca2+ channel enhancer, CaMKII, Proteasome activity, Alzheimer's disease, Cognitive function