BACE1-dependent cleavage of GABAA receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease

Abstract

Neural hyperexcitability has been clinically associated with amyloid-β (Aβ) pathology and cognitive impairment in Alzheimer's disease (AD). Here, we show that decreased GABA_A receptor (GABA_AR) currents are linked to hippocampal granule cell hyperexcitability in the AD mouse model APP23. Elevated levels of β-secretase (BACE1), the β-secretase responsible for generating Aβ peptides, lead to aberrant cleavage of GABA_AR β1/2/3 subunits in the brains of APP23 mice and AD patients. Moreover, BACE1-dependent cleavage of the β subunits leads to a decrease in GABA_AR-mediated inhibitory currents in BACE1 transgenic mice. Finally, we show that the neural hyperexcitability, Aβ load, and spatial memory deficit phenotypes of APP23 mice are significantly reduced upon the granule cell expression of a non-cleavable β3 subunit mutant. Collectively, our study establishes that BACE1-dependent cleavage of GABA_AR β subunits promotes the pathological hyperexcitability known to drive neurodegeneration and cognitive impairment in the AD brain, suggesting that prevention of the cleavage could slow disease progression.

Keywords: BACE1 substrate; GABRB; disinhibition; excitatory inhibitory balance; excitotoxicity; hyperactivity; hyperexcitability; β-secretase.