Resolve: Sub-maximal BACE1 Inhibition Selectively Restores NRG1-ErbB4 Signaling to PV Interneurons

BACE1 cleaves multiple substrates including NRG1, which is required for ErbB4-mediated PV interneuron maintenance. Full BACE1 inhibition has failed clinically, partly due to mechanism-based toxicities (BACE1 substrate effects). Sub-therapeutic APP cleavage inhibition might selectively rescue NRG1-ErbB4 signaling to PV cells while leaving Aβ generation largely intact — a paradoxically useful property if E/I imbalance is the primary driver of cognitive symptoms. Falsifiable prediction: BACE1 inhibitor NB-360 at 0.3× IC50 (APP substrate) in 5xFAD mice should increase PV interneuron NRG1-ErbB4 signaling (pErbB4/ErbB4 ratio) by ≥50%, restore gamma oscillation peak power by ≥35%, and improve novel object recognition index by ≥20%, without reducing Aβ42 by >10% in cortex. The selective NRG1 restoration mechanism must be confirmed by NRG1 type III ELISA.

$500.0K
OPEN
Confidence:
58%
Created: 2026-04-28

Linked Targets (1)

BACE1 Beta-secretase 1 PDB:6EQM0.57
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Detected Targets:
BACE1APP

3D Protein Structure

View 3D structure: BACE1 — PDB 6EQM

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

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Linked Hypotheses (1)

BACE1/NRG1 Axis Dysfunction Drives Excitatory/Inhibitory Imbalance via PV Intern NRG1/ERBB40.74