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.
Four days after a single application of inhibitor, the researchers measured secreted Aβ40 and Aβ42, and evaluated synaptic activity using an optical electrophysiology assay developed by biotech company Cellectricon in Mölndal, Sweden. In this assay, a calcium indicator is added to a culture of synaptically connected neurons. Neurons in one spot are stimulated with an electric field, and the researchers measure the response from connected cells.
Lanabecestat was most potent. It suppressed Aβ production by 70 percent, but also dampened synaptic activity by 15 percent, at all three doses tested. LY2886721 was milder. At the highest dose, it lowered Aβ by 57 percent and synaptic transmission by 39 percent. At the lower two doses, however, it cut Aβ levels by a bit less than 50 percent on average, and did not harm synaptic signaling. This implies that inhibition of less than 50 percent might preserve neuronal signaling, at least in this short-term paradigm, the authors note. The finding complements mouse studies that found low doses to be benign, while high doses damaged synaptic plasticity (Nov 2014 news).
Intriguingly, BACE Inhibitor IV was the least harmful to synapses. At the highest dose, it dropped Aβ production by more than 60 percent and muted electrical transmission by 16 percent. However, the middle dose, while still suppressing Aβ by about 60 percent, did not affect synaptic signaling. At the lowest dose, Aβ production fell by about 40 percent, while synaptic signaling actually strengthened by 13 percent. BACE Inhibitor IV is reputed to be selective for BACE1 over BACE2, while the other two are not (Stachel et al., 2004).
In addition, BACE inhibition may promote α cleavage of amyloid precursor protein, the authors noted. The sAPPα fragment has been found to protect neurons, perhaps explaining the better synaptic transmission (Mockett et al., 2017).
The Icelandic variant of APP lowers a person’s lifetime Aβ production by 30 percent and wards off AD, suggesting that low levels of inhibition over long time periods are sufficient for protection (Jul 2012 news; Jun 2017 news). However, it is unclear how early such therapy would have to be started. “It would also be interesting to explore if combinations of low-dose BACE inhibitors could result in additive effects on Aβ reduction without causing additive synaptic dysfunction,” the authors proposed.—Madolyn Bowman Rogers
- Verubecestat Negative Trial Data: What Does it Mean for BACE Inhibition?
- Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
- Cognitive Decline Trips Up API Trials of BACE Inhibitor
- Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors
- At High Doses, BACE1 Inhibitors Hinder Synaptic Plasticity in Mice
- Protective APP Mutation Found—Supports Amyloid Hypothesis
- More Support for Amyloid Hypothesis: Protective APP Mutation Lowers Aβ in Blood
- Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP. Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem. 2004 Dec 16;47(26):6447-50. PubMed.
- Mockett BG, Richter M, Abraham WC, Müller UC. Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα. Front Mol Neurosci. 2017;10:30. Epub 2017 Feb 7 PubMed.
- Satir TM, Agholme L, Karlsson A, Karlsson M, Karila P, Illes S, Bergström P, Zetterberg H. Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission. Alzheimers Res Ther. 2020 May 26;12(1):63. PubMed.