Zhou_2025_J.Neurochem_169_e70299

BACE1 is an indispensable enzyme for the production of beta-amyloid peptides by initiating the cleavage of amyloid precursor protein at the beta-secretase site. Targeting BACE1 inhibition is therefore a therapeutic strategy for treating patients with Alzheimer's disease. However, several clinical trials using brain-penetrable BACE1 inhibitors have failed due to a lack of efficacy. Previous studies, including our own, have shown that both global and neuron-specific BACE1 inhibition in mice leads to impairments in synaptic strength and spine density. In this study, we investigate the effects of BACE1 inhibition on activity-dependent synaptic vesicle exocytosis and endocytosis using a synapto-pHluorin mouse model. Our results demonstrate impaired synaptic release in BACE1-deficient mice. Furthermore, transcriptomic analysis reveals a significant downregulation of genes related to synapse structure and function. Pathway analysis suggests that BACE1 deficiency significantly downregulates neurexin-neuroligin pathway, which can modulate docking and release of synaptic vesicles at the presynaptic compartment. Our findings suggest that BACE1 inhibition may lead to deficits in synaptic vesicle exocytosis due to the downregulation of key synaptic proteins.