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 Apr 2;113(7):1051-1064.e6. Epub 2025 Feb 26 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.…More
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.…More
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 MirasLudwig Maximilians University
LMU Hospital
In this insightful study, Bi et al. identify a novel mechanism linking Aβ pathology to neuronal hyperexcitability via BACE1-mediated impairment of inhibitory GABAergic signaling. Best known for its role in Aβ generation, the BACE1 enzyme is shown here to aberrantly cleave the β1-3 subunits of GABAA receptors in an amyloid mouse model and in postmortem samples from AD patients, thereby diminishing inhibitory currents and promoting neuronal hyperactivity. Strikingly, the authors demonstrate that preventing this cleavage through a non-cleavable GABAA β3 subunit variant can restore inhibitory function. This intervention alleviated neuronal hyperactivity, led to reduced Aβ plaque burden, and improved memory performance in an APP transgenic mouse model. These findings provide direct evidence that BACE1 can promote circuit dysfunction and promote Aβ aggregation.…More
More broadly, this work reinforces the emerging view that neuronal hyperexcitability is not merely a bystander but an active contributor to AD progression (Roemer-Cassiano et al., 2025; Targa Dias Anastacio et al., 2022; Busche and Konnerth, 2015). Excessive neuronal firing has been observed in AD mouse models (often in proximity to Aβ plaques; Busche et al., 2008) and such aberrant activity has been linked to exacerbation of tau pathology (Wu et al., 2016). For example, hyperactive neurons can release greater amounts of pathological tau, potentially seeding its spread to connected brain areas (Roemer-Cassiano et al., 2025; Wu et al., 2016).
Consistent with this, our recent human imaging study found that Aβ deposition triggers an increase in functional connectivity (i.e., indicative of network hyperactivity) thereby driving accelerated spread of tau pathology across those hyperconnected regions (Roemer-Cassiano et al., 2025). In other words, Aβ-related neural hyperactivity appears to promote the spread of tau pathology, effectively linking the two hallmark pathologies.
Bi et al.’s findings add an important mechanistic dimension to this picture, illustrating one way that Aβ may trigger such detrimental neuronal hyperactivity. Their data suggest a vicious cycle: BACE1 levels become elevated in the AD brain (perhaps in response to early Aβ accumulation), leading to excessive cleavage of both APP and GABAA receptor subunits. The latter weakens inhibitory control and amplifies neuronal firing. This hyperexcitability, in turn, feeds back to promote increased Aβ production, ultimately accelerating AD progression. What the current study does not show, however, is how this BACE1-related upregulation of neuronal excitability and activity may contribute to tau secretion and spread, which should be tested in future studies.
The study also carries important therapeutic implications. By pinpointing a specific molecular cascade that links Aβ to network dysfunction, it highlights new opportunities to break this cycle. One approach is to directly dampen neuronal hyperactivity in at-risk patients—indeed, clinical trials are testing anti-epileptic drugs and neuromodulation (e.g., transcranial magnetic stimulation, focused ultrasound) to reduce aberrant brain activity in AD. Another approach would be to modulate BACE1 activity more selectively. The disappointing past trials of broad BACE1 inhibitors might be revisited with renewed hope if inhibitors can be tailored to spare key substrates like GABAA receptors while still curbing Aβ production. Overall, by elucidating how Aβ pathology undermines inhibitory circuits to promote AD progression, Bi et al. provide a compelling case that stabilizing neural networks—through restoring inhibition or fine-tuning BACE1’s actions—could help treat neuronal hyperexcitability and ultimately AD progression.
References:
Roemer-Cassiano SN, Wagner F, Evangelista L, Rauchmann BS, Dehsarvi A, Steward A, Dewenter A, Biel D, Zhu Z, Pescoller J, Gross M, Perneczky R, Malpetti M, Ewers M, Schöll M, Dichgans M, Höglinger GU, Brendel M, Jäkel S, Franzmeier N. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease. Sci Transl Med. 2025 Jan 22;17(782):eadp2564. Epub 2025 Jan 22 PubMed.
Targa Dias Anastacio H, Matosin N, Ooi L. Neuronal hyperexcitability in Alzheimer's disease: what are the drivers behind this aberrant phenotype?. Transl Psychiatry. 2022 Jun 22;12(1):257. PubMed.
Busche MA, Konnerth A. Neuronal hyperactivity--A key defect in Alzheimer's disease?. Bioessays. 2015 Jun;37(6):624-32. Epub 2015 Mar 14 PubMed.
Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science. 2008 Sep 19;321(5896):1686-9. PubMed.
Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RA, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016 Aug;19(8):1085-92. Epub 2016 Jun 20 PubMed.
View all comments by Sebastian N. Roemer-CassianoUniversity of Erlangen-Nuremberg
In his seminal publication of 1911 titled “Über eigenartige Krankheitsfälle des späteren Alters“ (On peculiar diseases of older age), Alois Alzheimer already noted that epileptiform activity is a common symptom of “his” disease, but it took about a century to unravel the underlying mechanisms. Previous work from the Kovacs lab at Harvard and the Palop/Mucke lab at University of California, San Francisco, showed that the activity of GABAergic interneurons is reduced in Alzheimer´s disease (AD) models due to a BACE1-mediated decline in the surface expression of Nav1.1. This subtype of voltage-gated Na+ channel is essential to drive action potential firing of GABAergic interneurons. The new study by Bi et al. examined what happens after the interneurons have fired and released GABA. The paper is very interesting, revealing an additional BACE1-dependent mechanism that impairs GABAergic inhibition, this time by clipping GABAA receptors, which serve as major effectors of synaptic inhibition in the postsynaptic neuron.…More
The authors make a compelling case for a fatal, disease-propelling interaction between BACE1 and postsynaptic GABAA receptor. Like any paper that opens a new venue of research, it gives also rise to several intriguing questions. For example, does the BACE1-induced loss of functional GABAA receptors on the postsynaptic site engender changes in spontaneous release properties on the presynaptic site, as suggested by the reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs)? Are synaptic and extrasynaptic GABAA receptors that mediate phasic and tonic inhibition, respectively, both cleaved by BACE1, thus equally reducing the two functionally distinct components of inhibition? In a similar vein, is the delta-subunit of GABAA receptors, which is essential to target GABAA receptors to extrasynaptic sites in hippocampal granule cells, a substrate of BACE1? How can we explain the apparent paradox that BACE1-deficient mice exhibit an epileptic phenotype, too, rather than being over-inhibited?
The final question relates to the conspicuous coincidence that, in the healthy adult brain, the axons of granule cells, the so-called mossy fibers, express high levels of BACE1 concomitant with the presence of presynaptic GABAA receptors, which regulate transmitter release from mossy fiber terminals. Assuming that the presynaptic GABAA receptors are also substrates of BACE1, would the high secretase level not predict a functionally relevant interaction with presynaptic GABAA receptors already under physiological conditions?
View all comments by Christian AlzheimerUniversity of Cambridge
A while back, we sought to characterize the electrophysiological phenotypes in one of the earliest presenilin transgenic mouse models (Zaman et al., 2000). LTP was enhanced in hippocampi of these mice, and this phenotype could be normalized with the use of the benzodiazepine diazepam (a GABAA positive modulator). One hypothesis of this GABAA receptor effect was that it was a consequence of the “build-up” of hyperexcitability, resulting in a compensatory response as seen in the brain slices.…More
Bi and colleagues’ paper provides a possible explanation of a mechanism for this change. Benzodiazepines bind to γ and α subunits and do not require β subunits for action on the receptor.
The epidemiological clinical data on the use of benzodiazepines, however, has been inconclusive in terms of benzodiazepines delaying cognitive decline, probably due to the adverse effects of these drugs especially in the elderly. Although there is an ongoing clinical trial using the non-GABAergic drug levetiracetam to test the notion of hyperexcitability of seizures being detrimental to disease progression, it would be important to establish at what stage of the disease this type of intervention would be useful.
References:
Zaman SH, Parent A, Laskey A, Lee MK, Borchelt DR, Sisodia SS, Malinow R. Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine. Neurobiol Dis. 2000 Feb;7(1):54-63. PubMed.
View all comments by Shahid ZamanMake a Comment
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