The neuropathological features of Alzheimer's disease (AD) are deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. Among these, neuro-inflammation is a common pathological substrate of neurodegenerative disease, such as AD, and Parkinson disease.

Herein, we tested whether the inhibition of bromodomain and extra-terminal domain (BET) protein, a critical regulators of transcription in neurons, could attenuate the neuronal cell death and amyloid beta aggregation using rat primary cortical neurons. We also investigated whether a BET inhibitor could prevent the inflammatory processes and cognitive decline in an animal model of AD.

The effects of BET inhibition on neuronal cell death were assessed in the followings:

– cell viability and reactive oxygen species generation;

– enzyme activity of tPA/PAI-1 measured by casein zymography;

– the signal pathways including BDNF/CREB and MAPKs using western blotting;

– the effects on inflammatory responses in an animal model of AD using immunohistochemistry.

JQ1, an inhibitor of Brd2/4 protein, significantly decreased the neuronal cell death in mixed cortical neurons in concentration-dependent manner but not in pure neurons. JQ1 increased the enzyme activity of tPA, which decreased the expression of Brd2 protein. JQ1 also decreased the ROS generation and decreased cleaved caspase-3 expression. Moreover, Brd2 inhibition by transfection of Brd2 siRNA reduced amyloid beta aggregation.

Our results suggested that BET inhibition might have therapeutic potential for AD. That is, Brd2 inhibition by JQ1 can prevent the neuronal cell death and neuroinflammation as well as amyloid beta aggregation through regulation of tPA/PAI-1 system.

The authors have not supplied their declaration of competing interest.