Abstract
BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer’s disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and excitability in the entorhinal–dentate circuitry.
Similar content being viewed by others
References
Barão S, Moechars D, Lichtenthaler SF, De Strooper B (2016) BACE1 physiological functions may limit its use as therapeutic target for Alzheimer’s disease. Trends Neurosci 39:158–169. https://doi.org/10.1016/j.tins.2016.01.003
Blume T, Filser S, Jaworska A et al (2018) BACE1 Inhibitor MK-8931 alters formation but not stability of dendritic spines. Front Aging Neurosci 10:229. https://doi.org/10.3389/fnagi.2018.00229
Bowden JB, Abraham WC, Harris KM (2012) Differential effects of strain, circadian cycle, and stimulation pattern on LTP and concurrent LTD in the dentate gyrus of freely moving rats. Hippocampus 22:1363–1370. https://doi.org/10.1002/hipo.20972
Bronzino JD, Abu-Hasaballah K, Austin-LaFrance RJ, Morgane PJ (1994) Maturation of long-term potentiation in the hippocampal dentate gyrus of the freely moving rat. Hippocampus 4:439–446. https://doi.org/10.1002/hipo.450040406
Bronzino JD, Blaise JH, Morgane PJ (1997) The paired-pulse index: a measure of hippocampal dentate granule cell modulation. Ann Biomed Eng 25:870–873
Cai H, Wang Y, McCarthy D et al (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4:233–234. https://doi.org/10.1038/85064
Cai Y, Xiong K, Zhang X-M et al (2010) β-Secretase-1 elevation in aged monkey and Alzheimer’s disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation. Eur J Neurosci 32:1223–1238. https://doi.org/10.1111/j.1460-9568.2010.07376.x
Cai Y, Zhang X-M, Macklin LN et al (2012) BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer’s disease: differential Aβ antibody labeling of early-onset axon terminal pathology. Neurotox Res 21:160–174. https://doi.org/10.1007/s12640-011-9256-9
Chauvet G, Berger TW (2002) Hierarchical model of the population dynamics of hippocampal dentate granule cells. Hippocampus 12:698–712. https://doi.org/10.1002/hipo.10106
Cooke SF, Wu J, Plattner F et al (2006) Autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse. J Physiol 574:805–818. https://doi.org/10.1113/jphysiol.2006.111559
Csicsvari J, Jamieson B, Wise KD, Buzsáki G (2003) Mechanisms of gamma oscillations in the hippocampus of the behaving rat. Neuron 37:311–322
de Jonge M, Racine RJ (1987) The development and decay of kindling-induced increases in paired-pulse depression in the dentate gyrus. Brain Res 412:318–328
Dislich B, Wohlrab F, Bachhuber T et al (2015) Label-free quantitative proteomics of mouse cerebrospinal fluid detects β-Site APP cleaving enzyme (BACE1) protease substrates in vivo. Mol Cell Proteomics 14:2550–2563. https://doi.org/10.1074/mcp.M114.041533
Dominguez D, Tournoy J, Hartmann D et al (2005) Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280:30797–30806. https://doi.org/10.1074/jbc.M505249200
Egan MF, Kost J, Tariot PN et al (2018) Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 378:1691–1703. https://doi.org/10.1056/NEJMoa1706441
Filser S, Ovsepian SV, Masana M et al (2015) Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry 77:729–739. https://doi.org/10.1016/j.biopsych.2014.10.013
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) β-secretase protein and activity are increased in the neocortex in alzheimer disease. Arch Neurol 59:1381–1389. https://doi.org/10.1001/archneur.60.6.828
Ghosh AK, Osswald HL (2014) BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease. Chem Soc Rev 43:6765–6813. https://doi.org/10.1039/c3cs60460h
Giusti-Rodríguez P, Gao J, Gräff J et al (2011) Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1). J Neurosci 31:15751–15756. https://doi.org/10.1523/JNEUROSCI.3588-11.2011
Haass C (2004) Take five—BACE and the gamma-secretase quartet conduct Alzheimer’ s amyloid beta-peptide generation. EMBO J 23:483–488. https://doi.org/10.1038/sj.emboj.7600061
Haass C, Selkoe DJ (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75:1039–1042
Harrison SM, Harper AJ, Hawkins J et al (2003) BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 24:646–655. https://doi.org/10.1016/S1044-7431(03)00227-4
Hemming ML, Elias JE, Gygi SP, Selkoe DJ (2009) Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One 4:e8477. https://doi.org/10.1371/journal.pone.0008477
Hessler S, Zheng F, Hartmann S et al (2015) β-secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion. J Neurosci 35:3298–3311. https://doi.org/10.1523/JNEUROSCI.3127-14.2015
Hitt BD, Jaramillo TC, Chetkovich DM, Vassar R (2010) BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization. Mol Neurodegener 5:31. https://doi.org/10.1186/1750-1326-5-31
Hu X, Zhou X, He W et al (2010) BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 30:8819–8829. https://doi.org/10.1523/JNEUROSCI.1334-10.2010
Hu X, He W, Luo X et al (2013) BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep 4:40–49. https://doi.org/10.1016/j.celrep.2013.06.005
Hussain I, Powell D, Howlett DR et al (1999) Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci 14:419–427. https://doi.org/10.1006/mcne.1999.0811
Huth T, Rittger A, Saftig P, Alzheimer C (2011) β-Site APP-cleaving enzyme 1 (BACE1) cleaves cerebellar Na+ channel β4-subunit and promotes Purkinje cell firing by slowing the decay of resurgent Na+ current. Pflugers Arch 461:355–371. https://doi.org/10.1007/s00424-010-0913-2
Isomura Y, Sirota A, Simal Ö et al (2006) Integration and segregation of activity in entorhinal-hippocampal subregions by neocortical slow oscillations. Neuron 52:871–882. https://doi.org/10.1016/j.neuron.2006.10.023
Jedlicka P, Papadopoulos T, Deller T et al (2009) Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo. Mol Cell Neurosci 41:94–100. https://doi.org/10.1016/j.mcn.2009.02.005
Jedlicka P, Deller T, Schwarzacher SW (2010) Computational modeling of GABAA receptor-mediated paired-pulse inhibition in the dentate gyrus. J Comput Neurosci 29:509–519. https://doi.org/10.1007/s10827-010-0214-y
Jedlicka P, Hoon M, Papadopoulos T et al (2011) Increased dentate gyrus excitability in neuroligin-2-deficient mice in vivo. Cereb cortex 21:357–367. https://doi.org/10.1093/cercor/bhq100
Jedlicka P, Owen M, Vnencak M et al (2012) Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo. Exp Brain Res 217:441–447. https://doi.org/10.1007/s00221-011-2911-9
Jedlicka P, Vnencak M, Jungenitz T et al (2015) Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo. Brain Struct Funct 220:47–58. https://doi.org/10.1007/s00429-013-0636-1
Jedlicka P, Muellerleile J, Schwarzacher S (2018) Synaptic Plasticity and excitation-inhibition balance in the dentate gyrus: insights from in vivo recordings in neuroligin-1, -2 and collybistin knockouts. Neural Plast 2018:2018
Kamenetz F, Tomita T, Hsieh H et al (2003) APP processing and synaptic function. Neuron 37:925–937. https://doi.org/10.1016/S0896-6273(03)00124-7
Kandalepas PC, Vassar R (2014) The normal and pathologic roles of the Alzheimer’s β-secretase, BACE1. Curr Alzheimer Res 11:441–449
Kandalepas PC, Sadleir KR, Eimer WA et al (2013) The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 126:329–352. https://doi.org/10.1007/s00401-013-1152-3
Kim DY, Carey BW, Wang H et al (2007) BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 9:755–764. https://doi.org/10.1038/ncb1602
Kim DY, Gersbacher MT, Inquimbert P, Kovacs DM (2011) Reduced sodium channel Na(v)1.1 levels in BACE1-null mice. J Biol Chem 286:8106–8116. https://doi.org/10.1074/jbc.M110.134692
Kobayashi D, Zeller M, Cole T et al (2008) BACE1 gene deletion: impact on behavioral function in a model of Alzheimer’s disease. Neurobiol Aging 29:861–873. https://doi.org/10.1016/j.neurobiolaging.2007.01.002
Krook-Magnuson E, Armstrong C, Bui A et al (2015) In vivo evaluation of the dentate gate theory in epilepsy. J Physiol 593:2379–2388. https://doi.org/10.1113/JP270056
Kuhn P-H, Koroniak K, Hogl S et al (2012) Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J 31:3157–3168. https://doi.org/10.1038/emboj.2012.173
Lacefield CO, Itskov V, Reardon T et al (2012) Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 22:106–116. https://doi.org/10.1002/hipo.20860
Laird FM, Cai H, Savonenko AV et al (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25:11693–11709. https://doi.org/10.1523/JNEUROSCI.2766-05.2005
Lee C-Y, Liou H-H (2013) GABAergic tonic inhibition is regulated by developmental age and epilepsy in the dentate gyrus. Neuroreport 24:515–519. https://doi.org/10.1097/WNR.0b013e32836205bc
Lehnert S, Hartmann S, Hessler S et al (2016) Ion channel regulation by β-secretase BACE1—enzymatic and non-enzymatic effects beyond Alzheimer’s disease. Channels 10:365–378. https://doi.org/10.1080/19336950.2016.1196307
Leutgeb JK, Leutgeb S, Moser M-B, Moser EI (2007) Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315:961–966. https://doi.org/10.1126/science.1135801
Li Z-X, Yu H-M, Jiang K-W (2013) Tonic GABA inhibition in hippocampal dentate granule cells: its regulation and function in temporal lobe epilepsies. Acta Physiol. https://doi.org/10.1111/apha.12148
Luo Y, Bolon B, Kahn S et al (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4:231–232. https://doi.org/10.1038/85059
Ma H, Lesné S, Kotilinek L et al (2007) Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc Natl Acad Sci USA 104:8167–8172. https://doi.org/10.1073/pnas.0609521104
Mattsson N, Rajendran L, Zetterberg H et al (2012) BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system. PLoS One 7:e31084. https://doi.org/10.1371/journal.pone.0031084
Müller UC, Deller T, Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18:281–298. https://doi.org/10.1038/nrn.2017.29
Nicoll RA, Roche KW (2013) Long-term potentiation: peeling the onion. Neuropharmacology 74:18–22. https://doi.org/10.1016/j.neuropharm.2013.02.010
O’Sullivan GA, Jedlicka P, Chen H-X, et al (2016) Forebrain-specific loss of synaptic GABA < inf> A</inf> receptors results in altered neuronal excitability and synaptic plasticity in mice. Mol Cell Neurosci. https://doi.org/10.1016/j.mcn.2016.01.010
Oehlrich D, Prokopcova H, Gijsen HJM (2014) The evolution of amidine-based brain penetrant BACE1 inhibitors. Bioorg Med Chem Lett 24:2033–2045. https://doi.org/10.1016/j.bmcl.2014.03.025
Ohno M (2016) Alzheimer’s therapy targeting the β-secretase enzyme BACE1: benefits and potential limitations from the perspective of animal model studies. Brain Res Bull 126:183–198. https://doi.org/10.1016/j.brainresbull.2016.04.007
Ohno M, Sametsky EA, Younkin LH et al (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’ s disease. Memory 41:27–33
Peters F, Salihoglu H, Rodrigues E et al (2018) BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathol. https://doi.org/10.1007/s00401-017-1804-9
Roberds SL, Anderson J, Basi G et al (2001) BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 10:1317–1324
Sachse CC, Kim YH, Agsten M et al (2013) BACE1 and presenilin/γ-secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels. FASEB J 27:2458–2467. https://doi.org/10.1096/fj.12-214056
Savonenko AV, Melnikova T, Laird FM et al (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci 105:5585–5590
Sinha S, Anderson JP, Barbour R et al (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537–540. https://doi.org/10.1038/990114
Sloviter RS (1991) Feedforward and feedback inhibition of hippocampal principal cell activity evoked by perforant path stimulation: GABA-mediated mechanisms that regulate excitability in vivo. Hippocampus 1:31–40. https://doi.org/10.1002/hipo.450010105
Stringer JL, Lothman EW (1989) Repetitive seizures cause an increase in paired-pulse inhibition in the dentate gyrus. Neurosci Lett 105:91–95
Vassar R (2014) BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther 6:89. https://doi.org/10.1186/s13195-014-0089-7
Vassar R, Bennett BD, Babu-Khan S et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741
Vassar R, Kuhn P-H, Haass C et al (2014) Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem 130:4–28. https://doi.org/10.1111/jnc.12715
Vnencak M, Paul MH, Hick M et al (2015) Deletion of the amyloid precursor-like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus. J Comp Neurol 523:1717–1729. https://doi.org/10.1002/cne.23766
Wang H, Song L, Laird F et al (2008) BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus. J Neurosci 28:8677–8681. https://doi.org/10.1523/JNEUROSCI.2440-08.2008
Wang H, Song L, Lee A et al (2010a) Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of alpha7 nicotinic acetylcholine receptors. J Neurosci 30:13808–13813. https://doi.org/10.1523/JNEUROSCI.1070-10.2010
Wang H, Song L, Lee A et al (2010b) Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of α 7 nicotinic acetylcholine receptors. J Neurosci 30:13808–13813. https://doi.org/10.1523/JNEUROSCI.1070-10.2010
Wang H, Megill A, Wong PC et al (2014) Postsynaptic target specific synaptic dysfunctions in the CA3 area of BACE1 knockout mice. PLoS One 9:e92279. https://doi.org/10.1371/journal.pone.0092279
Welzel AT, Maggio JE, Shankar GM et al (2014) Secreted amyloid β-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. Biochemistry 53:3908–3921
Willem M, Tahirovic S, Busche MA et al (2015) η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526:443–447. https://doi.org/10.1038/nature14864
Wilson CL, Khan SU, Engel J et al (1998) Paired pulse suppression and facilitation in human epileptogenic hippocampal formation. Epilepsy Res 31:211–230
Wong H-K, Sakurai T, Oyama F et al (2005) β Subunits of voltage-gated sodium channels are novel substrates of β-Site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J Biol Chem 280:23009–23017. https://doi.org/10.1074/jbc.M414648200
Yan R (2017) Physiological functions of the β-Site amyloid precursor protein cleaving enzyme 1 and 2. Front Mol Neurosci 10:97. https://doi.org/10.3389/fnmol.2017.00097
Yan R, Vassar R (2014) Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 13:319–329. https://doi.org/10.1016/S1474-4422(13)70276-X
Yan R, Gurney ME, Bienkowski MJ et al (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402:533–537. https://doi.org/10.1038/990107
Yan R, Fan Q, Zhou J, Vassar R (2016) Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease. Neurosci Biobehav Rev 65:326–340. https://doi.org/10.1016/j.neubiorev.2016.03.025
Yu J, Proddutur A, Elgammal FS et al (2013) Status epilepticus enhances tonic GABA currents and depolarizes GABA reversal potential in dentate fast-spiking basket cells. J Neurophysiol 109:1746–1763. https://doi.org/10.1152/jn.00891.2012
Zhu K, Peters F, Filser S, Herms J (2018a) Consequences of pharmacological BACE inhibition on synaptic structure and function. Biol Psychiatry. https://doi.org/10.1016/j.biopsych.2018.04.022
Zhu K, Xiang X, Filser S et al (2018b) Beta-Site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol Psychiatry 83:428–437. https://doi.org/10.1016/j.biopsych.2016.12.023
Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405. https://doi.org/10.1146/annurev.physiol.64.092501.114547
Funding
This study was funded by the Deutsche Forschungsgemeinschaft (DFG) (JE 528/6-1) and by the Alzheimer Forschung Initiative e.V. (15038).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Vnencak, M., Schölvinck, M.L., Schwarzacher, S.W. et al. Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo. Brain Struct Funct 224, 1279–1290 (2019). https://doi.org/10.1007/s00429-019-01836-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-019-01836-6