BACE inhibitors, with their ability to squelch Aβ production, seemed like a promising preventative therapy for Alzheimer’s disease. Unfortunately, their trials foundered, with some of them worsening cognition in an apparent class effect (Dec 2017 conference news ; Nov 2018 conference news ; Jul 2019 conference news ). Hoping the class can yet be salvaged, some scientists suggest that a low dose could nudge down Aβ while sparing cognition (Dec 2019 conference news ).
Researchers led by Henrik Zetterberg at the University of Gothenburg, Sweden, now say this just might work. In the May 26 Alzheimer’s Research & Therapy, they report that inhibiting Aβ production below a 50 percent threshold in cultured neurons harmed synaptic transmission, while inhibiting it by less left synaptic function intact.
Joint first authors Tugce Munise Satir and Lotta Agholme treated cultures of primary rat cortical neurons with the BACE inhibitor LY2886721 , BACE Inhibitor IV, or lanabecestat , at concentrations of 0.04, 0.3, or 3 μM. All three of these inhibitors were developed by Eli Lilly. LY2886721 was discontinued due to liver toxicity, while BACE Inhibitor IV was never tested in clinical trials, and lanabecestat was stopped in Phase 3 because of lack of efficacy and hints of cognitive harm.