Modeling presynaptic inhibition by the amyloid precursor protein demonstrates one potential mechanism for preventing runaway synaptic modification in Alzheimer's disease

INTRODUCTION Previous simulations of Hebbian associative memory models inspired the malignant synaptic growth hypothesis of Alzheimer's disease (AD), which suggests that cognitive impairments arise due to runaway synaptic modification resulting from poor separation between encoding and retrieval. METHODS We computationally model presynaptic inhibition by the recently identified interaction of soluble amyloid precursor protein alpha (sAPPα) with γ ‐aminobutyric acid type B receptor (GABA B R) as one potential biological mechanism that can enhance separation between encoding and retrieval. RESULTS Simulations predict that the dual effect of sAPPα on long‐term potentiation and presynaptic inhibition of glutamatergic synapses maintains effective associative memory function and prevents runaway synaptic modification. Moreover, computational modeling predicts that sAPPα, which interacts with the 1a isoform of GABA B R, is more effective than the GABA B R agonist baclofen at stabilizing associative memory. DISCUSSION Molecular mechanisms that enhance presynaptic inhibition, such as sAPPα‐GABA B R1a signaling, are potential therapeutic targets for preventing cognitive impairments in AD. Highlights Computational modeling of Hebbian associative memory provides a framework for understanding the functional basis of Alzheimer's disease. Soluble amyloid precursor protein (sAPPα) presynaptic activation of γ‐aminobutyric acid B (GABA B ) receptors prevents runaway synaptic modification in associative memory models. sAPPα is more effective than baclofen at stabilizing associative memory.