Adverse Neurologic Effect of BACE1 inhibitors in Alzheimer’s disease trials

TO THE EDITOR:

Egan et al.¹ reported adverse neurological effects including decreased memory and cognition in prodromal Alzheimer’s disease (AD) patients in a trail of verubecestat. Henley et al.² observed similar findings in a trial of atabecestat in presymptomatic AD subjects. These compounds inhibit β-site amyloid precursor protein (APP) cleaving enzyme (BACE). We conducted neurobiological studies of verbucestat and two other BACE inhibitors (lanabecestat and LY2886721). All 3 compounds significantly inhibited long-term potentiation (LTP), a key electrophysiological correlate of memory, in mouse hippocampus (Figure 1A). Two of the 3 inhibitors decreased paired-pulse facilitation, a measure of presynaptic neurotransmitter release, and all 3 reduced multi-pulse bursts that reflect both presynaptic and postsynaptic plasticity (Figure 1B, C). These data provide a mechanistic explanation for the impaired memory and cognition documented in these two human trials: BACE inhibitors interfere with the physiological processing of known neuronal substrates of BACE (e.g., neuregulin; Scn2b) required for neurotransmission. One needs to identify BACE1 inhibitors which selectively inhibit APP processing more than that of other substrates to enable safe, chronic inhibition of this amyloid-generating protease.

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 dose1.