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Rice HC, de Malmazet D, Schreurs A, Frere S, Van Molle I, Volkov AN, Creemers E, Vertkin I, Nys J, Ranaivoson FM, Comoletti D, Savas JN, Remaut H, Balschun D, Wierda KD, Slutsky I, Farrow K, De Strooper B, de Wit J. Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science. 2019 Jan 11;363(6423) PubMed.
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University of Hawaii
This is an intriguing paper reporting the novel finding that sAPPα, one of the secreted ectodomains of the amyloid precursor protein noted for its neurotrophic and neuroprotective actions, can act to regulate synaptic function via binding to a specific type B GABA receptor, GABAB-R1a, identified by a comprehensive proteomic screen. GABAB receptors are relatively slow, metabotropic, heteromeric neurotransmitter receptors and have significant presynaptic localization in brain, but are also present postsynaptically. GABAB receptors mediate much of the presynaptic inhibition driven by local GABA, the dominant inhibitory neurotransmitter in the brain. When present on excitatory inputs, excitation is suppressed, as shown in the present report for the 1a isoform, and when present on inhibitory GABAeric inputs as autoreceptors, the effect is disinhibition, promoting excitability. The finding that sAPPα regulates presynaptic inhibition and, in turn, presynaptic dynamics and synaptic transmission have ramifications for both physiological and perhaps pathological roles for APP beyond Aβ. Identification of a subdomain within sAPPα, specifically the extension domain (ExD), accounting for its high-affinity binding to and regulation of GABAB-R1a has implications for therapeutics. The reported findings raise a number of new questions, both for understanding the mechanisms at play and future application of the work.
These inhibitory metabotropic receptors are, of course, activated by GABA and couple differentially to adenylate cyclase, voltage-gated calcium channels and/or inward rectifying potassium channels, depending on locale and/or subtype. The question arises as to how sAPPα, and particularly ExD, regulates the activity and downstream intracellular coupling of GABAB-R1a through the latter’s sushi 1 domain, which is upstream of the GABA ligand binding domain. The effect of the GABAB-R antagonist might suggest an allosteric regulation of GABA binding. As for the regulation of presynaptic vesicle release, evident as changes in the frequency of miniature postsynaptic currents, might this be driven by negative regulation of presynaptic calcium channels or calcium levels? Perhaps a calcium imaging approach for presynaptic endings could be used (hippocampal cultures or isolated synaptosomes). In regard to synaptic plasticity, might the impact of sAPP differ for GABA-regulated pathways in different brain regions, possibly having the opposite action, namely an increase in excitability in certain pathways owing to GABAB-R1a serving as autoreceptors, for example? How might the regulation of sAPP release at these different pathways figure in? Moreover, changes in sAPP release with Alzheimer’s disease may translate into altered presynaptic GABAergic regulation via GABAB-R1a and hence altered neuronal excitability. Lastly, further refinement of the essential structural elements within the 34-amino acid ExD for GABAB-R1a regulation yielded a 9-amino acid sequence, though of lower affinity. This short peptide sequence could serve as a platform for eventually developing a unique small-molecule regulator of GABAB-R1a function in the brain.
View all comments by Robert NicholsBrigham and Women's Hospital and Harvard Medical School
APP has been shown to have a multifunctional role in both neurodevelopment and in the mature brain through its interactions with a variety of proteins. In this study, Rice et al. identify a novel role for APP in synaptic transmission through its interaction with a particular subunit of the GABA receptor. Importantly, the initial approach taken that identified the interaction was unbiased, and specifically searched for APP-interacting proteins present in the synaptic compartment. Through an elegant set of experiments, the authors identify a small region of the extracellular domain of APP that is sufficient to mediate the effects of the APP-GABAB-R1a interaction in vivo in the rodent brain.
View all comments by Tracy Young-PearseGladstone Institutes and University of California, San Francisco
This manuscript reinforces the notion that APP metabolites, including Aβ, participate in pre-and postsynaptic homeostatic mechanisms that regulate synaptic activity (for review, see Palop and Mucke, 2016) and identifies secreted APP as a key element regulating presynaptic release via GABAB receptors. Aβ reduces paired-pulse facilitation—a measure of increased release probability—and impairs long-term potentiation. Increased neurotransmitter release enhances the transfer of single-action potentials and synaptic depression, and may promote hyperactivity. Remarkably, Rice et al. now show that secreted APP may counteract theses effects by reducing release probability and enhancing paired-pulse facilitation. Although it is unclear whether secreted APP plays a role in the pathogenesis of AD, reducing presynaptic release to counteract AD-induced synaptic changes might be therapeutic. This manuscript also highlights the functional relevance of APP metabolites in synaptic function and the need to study APP and all its metabolites as a key molecule regulating synaptic function in health and disease.
References:
Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. Epub 2016 Nov 10 PubMed.
View all comments by Jorge PalopBaylor College of Medicine
Identification of sAPP receptor has been a long-standing interest for AD researchers, and a long list of potential receptors has been suggested over the past decade. In this elegant study, De Strooper, de Wit, and colleagues provide compelling evidence for GABAB as the cognate receptor for sAPP. The authors narrowed down the interaction of Sushi domains of GABAB to a 17 amino acid motif on the extension domain of sAPP, through which sAPP exerts a positive effect on GABAB receptor to reduce synaptic transmission. This finding, together with our earlier report showing that APP, highly expressed in GABAergic interneurons, critically mediates the balance between excitatory and inhibitory inputs through presynaptic GABAergic modulation (Wang et al., 2014), support a prominent role of APP in regulating GABAergic synaptic transmission. Since GABAB receptors mediate both pre- and postsynaptic inhibition, and may function as autoreceptors in GABAergic neurons or heteroreceptors in glutamate neurons, it would be interesting to further dissect these cellular mechanisms, and more importantly, understand how these mechanisms operate in the context of AD.
References:
Wang B, Wang Z, Sun L, Yang L, Li H, Cole AL, Rodriguez-Rivera J, Lu HC, Zheng H. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci. 2014 Oct 1;34(40):13314-25. PubMed.
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