Dunot J, Moreno S, Gandin C, Pousinha PA, Amici M, Dupuis J, Anisimova M, Winschel A, Uriot M, Petshow SJ, Mensch M, Bethus I, Giudici C, Hampel H, Wefers B, Wurst W, Naumann R, Ashby MC, Laube B, Zito K, Mellor JR, Groc L, Willem M, Marie H. APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors. Neuron. 2024 Aug 21;112(16):2708-2720.e9. Epub 2024 Jun 14 PubMed.

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  1. Several secretases are involved in the proteolytic processing of the amyloid precursor protein (APP) and, as a result, different proteolytic fragments are generated. How APP fragments interact and influence APP proteolytic processing merit profound research. In this interesting manuscript, Dunot and colleagues reported that AETA (Aη) fragments act as NMDAR modulators, and, conversely, that Aη generation depends on NMDAR activity. Previous studies indicated that APP and other APP fragments control NMDARs (see Pousinha et al., 2017; Rajão-Saraiva et al., 2023; Cousins et al., 2019; Hoe et al., 2009), including intracellular domain fragments via transcription-dependent mechanisms (Pousinha et al., 2017). 

    The employment of this complex machinery to generate APP fragments suggest that they play physiological roles. Thus, it is of interest to decipher whether activity of η-secretase is altered in AD, as previous data suggest. Anyhow, to get a whole view of APP processing in AD would be challenging, because of the necessary inclusion in the equation of the activity of α- and β-secretase, and even γ-secretase. Additionally, it is plausible that different APP fragments can modulate NMDAR in opposite ways, directly, or indirectly by competing each other, but also blocking each other.

    Full-length APP (Cuchillo-Ibañez et al., 2015) and APP C-terminal fragments are present in CSF (García-Ayllón, et al., 2017), some probably resulting from proteolytic processing by η-secretase. It would be interesting to determine the presence of Aη fragments in AD CSF, and whether these fragments form heterogeneous complexes with other soluble APP species, as we have reported previously. At the interstitial space, secreted Aη fragment could form complexes with soluble APP fragments, and with the membrane resident APP peptides, affecting APP physiological function.

    Dunot and colleagues claim that Aη enhances LTD via non-ionotropic activity of NMDARs because LTD still occurs after MK-801 (NMDARs blocker) treatment. There is evidence that while LTP is mainly driven by the activation of synaptic NMDARs ((Papouin et al., 2012). LTD requires the activation of both synaptic and extrasynaptic NMDARs (Liu et al., 2013). Given that MK-801 preferentially blocks synaptic over extrasynaptic NMDARs (McKay et al., 2013), it is also possible that the LTD exerted by Aη is driven by extrasynaptic NMDAR-mediated ionotropic activity. In the competition of Aη with NMDAR co-agonists to inhibit ionotropic activity, Dunot and colleagues use D-serine, the co-agonist of synaptic NMDARs; it will be of interest to study this with glycine, the co-agonist of extrasynaptic NMDARs (Papouin et al., 2012). Thus, the possibility that Aη modulates extrasynaptic NMDARs-mediated ionotropic activity should be studied.

    References:

    Pousinha PA, Mouska X, Raymond EF, Gwizdek C, Dhib G, Poupon G, Zaragosi LE, Giudici C, Bethus I, Pacary E, Willem M, Marie H. Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein. Elife. 2017 Jul 6;6 PubMed.

    Rajão-Saraiva J, Dunot J, Ribera A, Temido-Ferreira M, Coelho JE, König S, Moreno S, Enguita FJ, Willem M, Kins S, Marie H, Lopes LV, Pousinha PA. Age-dependent NMDA receptor function is regulated by the amyloid precursor protein. Aging Cell. 2023 Mar;22(3):e13778. Epub 2023 Jan 26 PubMed.

    Cousins SL, Hoey SE, Anne Stephenson F, Perkinton MS. Amyloid precursor protein 695 associates with assembled NR2A- and NR2B-containing NMDA receptors to result in the enhancement of their cell surface delivery. J Neurochem. 2009 Dec;111(6):1501-13. PubMed.

    Hoe HS, Fu Z, Makarova A, Lee JY, Lu C, Feng L, Pajoohesh-Ganji A, Matsuoka Y, Hyman BT, Ehlers MD, Vicini S, Pak DT, Rebeck GW. The effects of amyloid precursor protein on postsynaptic composition and activity. J Biol Chem. 2009 Mar 27;284(13):8495-506. PubMed.

    Cuchillo-Ibañez I, Lopez-Font I, Boix-Amorós A, Brinkmalm G, Blennow K, Molinuevo JL, Sáez-Valero J. Heteromers of amyloid precursor protein in cerebrospinal fluid. Mol Neurodegener. 2015 Jan 8;10:2. PubMed.

    García-Ayllón MS, Lopez-Font I, Boix CP, Fortea J, Sánchez-Valle R, Lleó A, Molinuevo JL, Zetterberg H, Blennow K, Sáez-Valero J. C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease. Sci Rep. 2017 May 30;7(1):2477. PubMed.

    Liu DD, Yang Q, Li ST. Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons. Brain Res Bull. 2013 Apr;93:10-6. Epub 2012 Dec 25 PubMed.

    Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, Groc L, Pollegioni L, Mothet JP, Oliet SH. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell. 2012 Aug 3;150(3):633-46. PubMed.

    McKay S, Bengtson CP, Bading H, Wyllie DJ, Hardingham GE. Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure. Neuropharmacology. 2013 Nov;74:119-25. Epub 2013 Feb 10 PubMed.

    View all comments by Javier Saez-Valero

  2. This report provides exciting new insights into the potential physiological role of a proteolytic cleavage fragment of amyloid precursor protein (APP), known as Aη (AETA), which was first discovered by the authors about a decade ago (Willem et al., 2015). APP is one of the most abundant proteins found in synaptic boutons. In sophisticated experiments, the authors show that Aη is a novel NMDA receptor regulator. It competes at the co-agonist binding site. Aη not only reduced NMDAR ionotropic activity but also promoted ion-flux independent activity. As such, long term depression (LTD) occurs at synapses and dendritic spines shrink. 

    Previously the authors demonstrated that both genetic and pharmacological inhibition of BACE1 activity results in a large increase in η-secretase cleavage products of APP, such as CTF-η and Aη-α. They also found that BACE1 inhibition resulted in a reduction of long-term potentiation (LTP) and that recombinant or synthetic Aη-α treatment lowered LTP ex vivo and in vivo. With the current report, BACE1 inhibition using LY2811376 increased endogenous Aη-α. BACE1 inhibition, at the tested dose of 100 mg/kg (LY2811376), did increase synaptic LTD with an associated twofold increase in Aη-α. This could be a contributing mechanism behind the reported cognitive worsening of past BACE1 inhibitor trial participants. It is important to note that the BACE1 inhibitor in this study is at an exceptionally high dose that was shown to decrease cortical Aβ in mice by nearly 70 percent (May et al., 2011). It will be enlightening to see if low-dose BACE inhibition, i.e. decreasing BACE1 by only 30 percent, as has been proposed in the revival of BACE inhibitors, has any deleterious effects on Aη-mediated LTD (and LTP) changes. At these lower doses, presumably such effects would be mitigated.

    This report provides supporting evidence that implicates APP in the physiological function of NMDARs and a possible role in aging-related NMDAR changes as well as pathological changes in Alzheimer’s disease. Further studies are necessary to probe the possible pathophysiological role of Aη on NMDARs in these settings, as well as changes that might occur with low-dose BACE1 inhibition. Results of future studies will have important therapeutic implications.

    References:

    Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LD, Moore S, Daria A, Hampel H, Müller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E, Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Müller U, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015 Oct 15;526(7573):443-7. Epub 2015 Aug 31 PubMed.

    May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith Labell E, Gonzales CR, Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg Hall D, Friedrich S, Citron M, Audia JE. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16. PubMed.

    View all comments by Justyna Dobrowolska Zakaria

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