Abstract
BACE1 initiates production of β-amyloid peptides (Aβ), which is associated with cognitive dysfunction in Alzheimer’s disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aβ 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.
Highlights
Typical clinical symptoms of Alzheimer’s disease (AD) are gradual loss of memory and cognitive ability [1,2,3,4]
We discovered that synaptic vesicles were not properly docked on the synaptic active zone, and significantly fewer synaptic vesicles were in the readily releasable pool (RRP) in BACE1-null mice or mice treated with BACE1 inhibitors such as Verubecestat (MK-8931) and Lanabecestat (AZD3293)
It is noted that the expressions of both PSD-95 and metabotropic glutamate receptor 1 (mGluR1) were age-dependent, and their lower levels are correlated with reduced synaptic function in aging mice [25, 26]
Summary
Typical clinical symptoms of Alzheimer’s disease (AD) are gradual loss of memory and cognitive ability [1,2,3,4]. BACE1, β-site amyloid precursor protein cleaving enzyme 1, was discovered to be the sole β-secretase that initiates the production of Aβ [9,10,11,12,13], and BACE1 inhibition or deletion reduces amyloid deposition in brains of AD patients and animal models [14, 15]. When BACE1 is ablated in adult conditional knockout mice, despite the reversal of preexisting amyloid plaques, LTP reduction is noted [20, 21]. This LTP reduction is seen in the non-AD background, in line with the observation that BACE1 is required for hippocampal axonal organization [22]. Global and dramatic inhibition of BACE1 over a long period appears to compromise the benefit of Aβ reduction due to mechanistic side effects associated with synaptic impairment
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