A novel tacrine-dihydropyridine hybrid (-)SCR1693 induces tau dephosphorylation and inhibits Aβ generation in cells

AChE inhibitors are the first choice for the treatment of Alzheimer׳s disease (AD), but they could only delay the progression of cognitive and behavioral dysfunction, and fail to reverse neuronal damage. Calcium channel blockers have been identified to have protective effect on neurons. Thus, therapy targeting both AChE and calcium channels is supposed to be more effective in AD treatment. In the present study, we explored the effect of a synthesized juxtaposition of an AChE inhibitor and a Calcium channel blocker (named (-)SCR1693) on tau phosphophorylation and Aβ generation. The results showed that: (1) Compared with higher concentrations, (-)SCR1693 incubation in low concentrations such as 0.4, 2, 4 μM for 24 h did not affect the cell viability of HEK293/tau (HEK293 cells stably transfected with human tau40) and N2a/APP (N2a cells stably transfected with human APP) cells; (2) long-term treatment of cells with (-)SCR1693 (0.4, 2, 5 μM) (24 h) induced tau dephosphorylation and reduced the total tau level in HEK293/tau cells. Short-term treatment (6 h) also resulted in tau dephosphorylation, but did not reduce the total tau level; and (3) (-)SCR1693 (0.4, 2, 4 μM) incubation inhibited Aβ generation and release dramatically in N2a/APP cells. We conclude that the novel tacrine-dihydropyridine hybrid (-)SCR1693 in low concentrations could reduce total and phosphorylated tau levels, inhibit the generation and release of Aβ in cells. Thus, (-)SCR1693 may be a potential candidate for effectively treating AD.