Bi D, Bao H, Yang X, Wu Z, Yang X, Xu G, Liu X, Wan Z, Liu J, He J, Wen L, Jing Y, Zhu R, Long Z, Rong Y, Wang D, Wang X, Xiong W, Huang G, Gao F, Shen Y. BACE1-dependent cleavage of GABAA receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease. Neuron. 2025 Feb 25; Epub 2025 Feb 25 PubMed.
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German Center for Neurodegenerative Diseases (DZNE)
This is a very interesting story, adding GABAAR subunits to the growing list of BACE1 substrates. In some of the experiments, changes in BACE1 activity had surprisingly strong effects on the cleavage and activity of the receptor/subunits. I would love to see whether clinically used BACE1-targeted inhibitors show effects similar to those of the knockout. If yes, we need to consider whether GABAAR-related functional changes contribute to the cognitive side effects seen for the high doses of BACE inhibitors used in previous clinical trials.
View all comments by Stefan LichtenthalerUniversity of Castilla-La Mancha
I was not surprised by the findings. We know that the GABAergic system is altered in AD, and this includes at least alteration/loss of interneurons and alteration of GABA receptors. We have been working quite a bit, and published some articles, on how GABAB receptors are downregulated in animal models of AD, using histological and ultrastructural techniques. We have also been working for the last three years on the potential alteration of GABAA receptors and found that the alpha1 subunit of GABAA receptors is downregulated in GABAergic synapses and have some evidence that β subunits can be altered. This information is not ready for publishing because we are now concentrated in glutamatergic receptors and do not have enough time and people to complete the experiments.
This article by Bi and colleagues confirms what I had in mind. The role of GABAA receptors is to inhibit neurons. It is known that AD causes hyperexcitation, which may occur by increasing the number or activation of glutamate receptors, by decreasing the number or activation of GABAA receptors, or by both at the same time. This paper demonstrates that BACE1 cleaves GABAA β1/2/3 subunits, resulting in decreased GABAAR-mediated inhibitory currents. Therefore, this cleavage promotes neural hyperexcitability, which is involved in the progression of cognitive impairments.
The article is fantastic and elegantly demonstrates their findings, thus opening a new avenue for therapeutic intervention to prevent cleavage of β subunits of GABAA and slow AD progression.
For sure, we will also have to take into consideration glutamate receptors and how to prevent their hyperactivity, but at least finding this new target is a good step to understand the pathological mechanisms taking place in AD and why it is such a complex neurodegenerative disease.
View all comments by Rafael Luján MirasMake a Comment
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