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Comment
. 2019 Jul 25;381(4):388.
doi: 10.1056/NEJMc1906679.

Verubecestat for Prodromal Alzheimer's Disease

Shaomin Li  1 , Lei Liu  1 , Dennis Selkoe  1
Affiliations
Comment

Verubecestat for Prodromal Alzheimer's Disease

Shaomin Li et al. N Engl J Med. .
No abstract available

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Figures

Figure. 1
Figure. 1
Verubecestat, lanabecestat and LY2886721 impair synaptic plasticity in mouse hippocampus. A. All 3 BACE inhibitors decrease LTP in hippocampal CA1 slices after exposure for 5 hr: verubecestat 123 ± 8% (n=6) vs. vehicle (DMSO) 152 ± 7% (n=6), p<0.01; lanabecestat 134 ± 8% (n=7) vs. vehicle (DMSO) 155 ± 7% (n=7), p<0.05; LY2886721 132 ± 3% (n=6) vs. vehicle (DMSO) 151 ± 8% (n=6), p<0.05 (means ± SEM; unpaired Student’s t-test). B. Two of the 3 inhibitors impair paired-pulse facilitation (60 ms interstimulus intervals): verubecestat 1.23 ± 0.05 vs. vehicle (DMSO) 1.72 ± 0.075, p<0.001; LY2886721 vs. vehicle (DMSO) 1.45 ± 0.05, p<0.01. C. All 3 inhibitors significantly impair short-term plasticity in burst stimulations, especially by the 3rd-8th pulses. Insets in B-C represent typical field excitatory postsynaptic potentials (fEPSPs) recorded in vehicle (black) or after 5 hr verubecestat exposure (red). Horizontal calibration bar, 20 ms; vertical bar, 0.5 mV. Note that 10 μM doses enabled sufficient slice penetration in vitro to quantify acute effects; verubecestat administered chronically to rats at 25 mg/kg/day for 3 mo resulted in >1 μM free compound in brain 3 hr after final dose.
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References

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