BACE1 controls synaptic function through modulating release of synaptic vesicles

BACE1 initiates production of beta-amyloid peptides (A beta), which is associated with cognitive dysfunction in Alzheimer's disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in A beta deposition, they fail to improve cognitive function in patients, largely due to its role in synaptic function. We show that BACE1 is required for optimal release of synaptic vesicles. BACE1 deficiency or inhibition decreases synaptic vesicle docking in the synaptic active zones. Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. To counterbalance this synaptic deficit, we discovered that BACE1-null mice treated with positive allosteric modulators (PAMs) of metabotropic glutamate receptor 1 (mGluR1), whose levels were reduced in BACE1-null mice and significantly improved long-term potentiation and cognitive behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients.

Automated summary

Our study reveals the crucial role of BACE1 in synaptic vesicle release and the impact of BACE1 inhibitors on synaptic vesicle docking in the active zones. Additionally, BACE1 deficiency results in severe reduction in hippocampal LTP and learning behaviors in mice.