Transmission of pain signals from primary sensory neurons to secondary neurons of the central nervous system is critically dependent on presynaptic voltage-gated calcium channels. Calcium channel-binding domain 3 (CBD3), derived from the collapsin response mediator protein 2 (CRMP2), is a peptide aptamer that is effective in blocking N-type voltage-gated calcium channel (CaV2.2) activity. We previously reported that recombinant adeno-associated virus (AAV)-mediated restricted expression of CBD3 affixed to enhanced green fluorescent protein (EGFP) in primary sensory neurons prevents the development of cutaneous mechanical hypersensitivity in a rat neuropathic pain model. In this study, we tested whether this strategy is effective in treating established pain. We constructed AAV6-EGFP-CBD3A6K (AAV6-CBD3A6K) expressing a fluorescent CBD3A6K (replacing A to K at position 6 of CBD3 peptide), which is an optimized variant of the parental CBD3 peptide that is a more potent blocker of CaV2.2. Delivery of AAV6-CBD3A6K into lumbar (L) 4 and 5 dorsal root ganglia (DRG) of rats 2 weeks following tibial nerve injury (TNI) induced transgene expression in neurons of these DRG and their axonal projections, accompanied by attenuation of pain behavior. We additionally observed that the increased CaV2.2α1b immunoreactivity in the ipsilateral spinal cord dorsal horn and DRG following TNI was significantly normalized by AAV6-CBD3A6K treatment. Finally, the increased neuronal activity in the ipsilateral dorsal horn that developed after TNI was reduced by AAV6-CBD3A6K treatment. Collectively, these results indicate that DRG-restricted AAV6 delivery of CBD3A6K is an effective analgesic molecular strategy for the treatment of established neuropathic pain.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Molecular Neurobiology Open Access 18 January 2021
Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice
Molecular Brain Open Access 09 April 2020
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Dzau VJ, Pizzo PA. Relieving pain in America: insights from an Institute of Medicine committee. JAMA. 2014;312:1507–8. https://doi.org/10.1001/jama.2014.12986
Loeser JD. Relieving pain in America. Clin J Pain. 2012;28:185–6. https://doi.org/10.1097/AJP.0b013e318230f6c1
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–84. https://doi.org/10.1016/j.cell.2009.09.028
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32. https://doi.org/10.1146/annurev.neuro.051508.135531
Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006;52:77–92. https://doi.org/10.1016/j.neuron.2006.09.021
Bucci G, Mochida S, Stephens GJ. Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca(2)+ channel peptides. J Physiol. 2011;589:3085–101. https://doi.org/10.1113/jphysiol.2010.204735
Bell TJ, Thaler C, Castiglioni AJ, Helton TD, Lipscombe D. Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron. 2004;41:127–38.
Altier C, Dale CS, Kisilevsky AE, Chapman K, Castiglioni AJ, Matthews EA, et al. Differential role of N-type calcium channel splice isoforms in pain. J Neurosci. 2007;27:6363–73. https://doi.org/10.1523/JNEUROSCI.0307-07.2007
Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci. 2009;29:4076–88. https://doi.org/10.1523/JNEUROSCI.0356-09.2009
Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004:reE14 https://doi.org/10.1126/stke.2522004re14
Tyagarajan S, Chakravarty PK, Park M, Zhou B, Herrington JB, Ratliff K, et al. A potent and selective indole N-type calcium channel (Ca(v)2.2) blocker for the treatment of pain. Bioorg Med Chem Lett. 2011;21:869–73. https://doi.org/10.1016/j.bmcl.2010.11.067
Liang M, Yin XL, Shi HB, Li CY, Li XY, Song NY, et al. Bilirubin augments Ca(2+) load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels. Sci Rep. 2017;7:431 https://doi.org/10.1038/s41598-017-00275-9
Norton RS, McDonough SI. Peptides targeting voltage-gated calcium channels. Curr Pharm Des. 2008;14:2480–91.
Perret D, Luo ZD. Targeting voltage-gated calcium channels for neuropathic pain management. Neurotherapeutics. 2009;6:679–92. https://doi.org/10.1016/j.nurt.2009.07.006
Pexton T, Moeller-Bertram T, Schilling JM, Wallace MS. Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert Opin Investig Drugs. 2011;20:1277–84. https://doi.org/10.1517/13543784.2011.600686
Vink S, Alewood PF. Targeting voltage-gated calcium channels: developments in peptide and small-molecule inhibitors for the treatment of neuropathic pain. Br J Pharmacol. 2012;167:970–89. https://doi.org/10.1111/j.1476-5381.2012.02082.x
Zamponi GW. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov. 2016;15:19–34. https://doi.org/10.1038/nrd.2015.5
Park J, Luo ZD. Calcium channel functions in pain processing. Channels. 2010;4:510–7.
Patel R, Montagut-Bordas C, Dickenson AH. Calcium channel modulation as a target in chronic pain control. Br J Pharmacol. 2018;175:2173–84. https://doi.org/10.1111/bph.13789
McGivern JG. Targeting N-type and T-type calcium channels for the treatment of pain. Drug Discov Today. 2006;11:245–53. https://doi.org/10.1016/S1359-6446(05)03662-7
Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex. Nat Med. 2011;17:822–9. https://doi.org/10.1038/nm.2345
Moutal A, Wang Y, Yang X, Ji Y, Luo S, Dorame A, et al. Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. Pain. 2017;158:2203–21. https://doi.org/10.1097/j.pain.0000000000001026
Hoppe-Seyler F, Crnkovic-Mertens I, Tomai E, Butz K. Peptide aptamers: specific inhibitors of protein function. Curr Mol Med. 2004;4:529–38.
Brittain JM, Piekarz AD, Wang Y, Kondo T, Cummins TR, Khanna R. An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem. 2009;284:31375–90. https://doi.org/10.1074/jbc.M109.009951
Francois-Moutal L, Wang Y, Moutal A, Cottier KE, Melemedjian OK, Yang X, et al. A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. Pain. 2015;156:1247–64. https://doi.org/10.1097/j.pain.0000000000000147
Xie JY, Chew LA, Yang X, Wang Y, Qu C, Wang Y, et al. Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential. Pain. 2016;157:2124–40. https://doi.org/10.1097/j.pain.0000000000000628
Simms BA, Zamponi GW. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron. 2014;82:24–45. https://doi.org/10.1016/j.neuron.2014.03.016
Chi XX, Schmutzler BS, Brittain JM, Wang Y, Hingtgen CM, Nicol GD, et al. Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J Cell Sci. 2009;122:4351–62. https://doi.org/10.1242/jcs.053280
Fischer G, Pan B, Vilceanu D, Hogan QH, Yu H. Sustained relief of neuropathic pain by AAV-targeted expression of CBD3 peptide in rat dorsal root ganglion. Gene Ther. 2014;21:44–51. https://doi.org/10.1038/gt.2013.56
Piekarz AD, Due MR, Khanna M, Wang B, Ripsch MS, Wang R, et al. CRMP-2 peptide mediated decrease of high and low voltage-activated calcium channels, attenuation of nociceptor excitability, and anti-nociception in a model of AIDS therapy-induced painful peripheral neuropathy. Mol Pain. 2012;8:54 https://doi.org/10.1186/1744-8069-8-54
Yu H, Fischer G, Ferhatovic L, Fan F, Light AR, Weihrauch D, et al. Intraganglionic AAV6 results in efficient and long-term gene transfer to peripheral sensory nervous system in adult rats. PLoS ONE. 2013;8:e61266 https://doi.org/10.1371/journal.pone.0061266
Hughes DI, Scott DT, Todd AJ, Riddell JS. Lack of evidence for sprouting of Abeta afferents into the superficial laminas of the spinal cord dorsal horn after nerve section. J Neurosci. 2003;23:9491–9.
Yu H, Pan B, Weyer A, Wu HE, Meng J, Fischer G, et al. CaMKII controls whether touch is painful. J Neurosci. 2015;35:14086–102. https://doi.org/10.1523/JNEUROSCI.1969-15.2015
D’Arco M, Margas W, Cassidy JS, Dolphin AC. The upregulation of alpha2delta-1 subunit modulates activity-dependent Ca2+signals in sensory neurons. J Neurosci. 2015;35:5891–903. https://doi.org/10.1523/JNEUROSCI.3997-14.2015
Lu SG, Zhang XL, Luo ZD, Gold MS. Persistent inflammation alters the density and distribution of voltage-activated calcium channels in subpopulations of rat cutaneous DRG neurons. Pain. 2010;151:633–43. https://doi.org/10.1016/j.pain.2010.08.030
Hoppa MB, Lana B, Margas W, Dolphin AC, Ryan T. A. alpha2delta expression sets presynaptic calcium channel abundance and release probability. Nature. 2012;486:122–5. https://doi.org/10.1038/nature11033
Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, Catterall WA. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron. 1992;9:1099–115.
Cizkova D, Marsala J, Lukacova N, Marsala M, Jergova S, Orendacova J, et al. Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury. Exp Brain Res. 2002;147:456–63. https://doi.org/10.1007/s00221-002-1217-3
Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010;11:823–36. https://doi.org/10.1038/nrn2947
Wilson SM, Brittain JM, Piekarz AD, Ballard CJ, Ripsch MS, Cummins TR, et al. Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex. Channels. 2011;5:449–56. https://doi.org/10.4161/chan.5.5.17363
Xiang H, Liu Z, Wang F, Xu H, Roberts C, Fischer G, et al. Primary sensory neuron-specific interference of TRPV1 signaling by AAV-encoded TRPV1 peptide aptamer attenuates neuropathic pain. Mol Pain. 2017;13:1744806917717040 https://doi.org/10.1177/1744806917717040
Swett JE, Torigoe Y, Elie VR, Bourassa CM, Miller PG. Sensory neurons of the rat sciatic nerve. Exp Neurol. 1991;114:82–103.
Heinke B, Balzer E, Sandkuhler J. Pre- and postsynaptic contributions of voltage-dependent Ca2+channels to nociceptive transmission in rat spinal lamina I neurons. Eur J Neurosci. 2004;19:103–11.
Rycroft BK, Vikman KS, Christie MJ. Inflammation reduces the contribution of N-type calcium channels to primary afferent synaptic transmission onto NK1 receptor-positive lamina I neurons in the rat dorsal horn. J Physiol. 2007;580:883–94. https://doi.org/10.1113/jphysiol.2006.125880
Chai Z, Wang C, Huang R, Wang Y, Zhang X, Wu Q, et al. CaV2.2 gates calcium-independent but voltage-dependent secretion in mammalian sensory neurons. Neuron. 2017;96:1317–26. https://doi.org/10.1016/j.neuron.2017.10.028. e1314
Zhang FX, Gadotti VM, Souza IA, Chen L, Zamponi GW. BK potassium channels suppress cavalpha2delta subunit function to reduce inflammatory and neuropathic pain. Cell Rep. 2018;22:1956–64. https://doi.org/10.1016/j.celrep.2018.01.073
Bezprozvanny I, Zhong P, Scheller RH, Tsien RW. Molecular determinants of the functional interaction between syntaxin and N-type Ca2+ channel gating. Proc Natl Acad Sci USA. 2000;97:13943–8. https://doi.org/10.1073/pnas.220389697
Cassidy JS, Ferron L, Kadurin I, Pratt WS, Dolphin AC. Functional exofacially tagged N-type calcium channels elucidate the interaction with auxiliary alpha2delta-1 subunits. Proc Natl Acad Sci USA. 2014;111:8979–84. https://doi.org/10.1073/pnas.1403731111
Diverse-Pierluissi M, Dunlap K. Interaction of convergent pathways that inhibit N-type calcium currents in sensory neurons. Neuroscience. 1995;65:477–83.
Kadurin I, Rothwell SW, Lana B, Nieto-Rostro M, Dolphin AC. LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary alpha2delta-1 subunit. Sci Rep. 2017;7:43802 https://doi.org/10.1038/srep43802
Leroy J, Richards MW, Butcher AJ, Nieto-Rostro M, Pratt WS, Davies A, et al. Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties. J Neurosci. 2005;25:6984–96. https://doi.org/10.1523/JNEUROSCI.1137-05.2005
Omote K, Kawamata M, Satoh O, Iwasaki H, Namiki A. Spinal antinociceptive action of an N-Type voltage-dependent calcium channel blocker and the synergistic interaction with morphine. Anesthesiology. 1996;84:636–43.
Sheng ZH, Rettig J, Cook T, Catterall WA. Calcium-dependent interaction of N-type calcium channels with the synaptic core complex. Nature. 1996;379:451–4. https://doi.org/10.1038/379451a0
Ju W, Li Q, Allette YM, Ripsch MS, White FA & Khanna R. Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide. J Neurochem. https://doi.org/10.1111/jnc.12070 (2012).
Ripsch MS, Ballard CJ, Khanna M, Hurley JH, White FA, Khanna R. A Peptide uncoupling crmp-2 from the presynaptic ca(2+) channel complex demonstrates efficacy in animal models of migraine and aids therapy-induced neuropathy. Transl Neurosci. 2012;3:1–8. https://doi.org/10.2478/s13380-012-0002-4
Ip JP, Fu AK, Ip NY. CRMP2: functional roles in neural development and therapeutic potential in neurological diseases. Neuroscientist. 2014;20:589–98. https://doi.org/10.1177/1073858413514278
Suzuki Y, Nakagomi S, Namikawa K, Kiryu-Seo S, Inagaki N, Kaibuchi K, et al. Collapsin response mediator protein-2 accelerates axon regeneration of nerve-injured motor neurons of rat. J Neurochem. 2003;86:1042–50.
Kamiya Y, Saeki K, Takiguchi M. CDK5, CRMP2 and NR2B in spinal dorsal horn and dorsal root ganglion have different role in pain signaling between neuropathic pain model and inflammatory pain model. Eur J Anaesthesiol. 2013;30:214.
Zhang JN, Koch JC. Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. Neural Regen Res. 2017;12:692–5. https://doi.org/10.4103/1673-5374.206631
Moutal A, Luo S, Largent-Milnes, TM, Vanderah TW, Khanna R. Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain. Neurobiol Pain. In press, https://doi.org/10.1016/j.ynpai.2018.1007.1003 (2018).
Chapman V, Suzuki R, Dickenson AH. Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5-L6. J Physiol. 1998;507:881–94.
Takaishi K, Eisele JH Jr., Carstens E. Behavioral and electrophysiological assessment of hyperalgesia and changes in dorsal horn responses following partial sciatic nerve ligation in rats. Pain. 1996;66:297–306.
Palecek J, Paleckova V, Dougherty PM, Carlton SM, Willis WD. Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy. J Neurophysiol. 1992;67:1562–73. https://doi.org/10.1152/jn.19220.127.116.112
Laird JM, Bennett GJ. An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol. 1993;69:2072–85. https://doi.org/10.1152/jn.1918.104.22.1682
Brustovetsky T, Pellman JJ, Yang XF, Khanna R, Brustovetsky N. Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+exchanger and regulates their functional activity. J Biol Chem. 2014;289:7470–82. https://doi.org/10.1074/jbc.M113.518472
Dustrude ET, Wilson SM, Ju W, Xiao Y, Khanna R. CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J Biol Chem. 2013;288:24316–31. https://doi.org/10.1074/jbc.M113.474924
Brittain JM, Pan R, You H, Brustovetsky T, Brustovetsky N, Zamponi GW, et al. Disruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion model. Channels (Austin) 2012;6:52–59.
Kanellopoulos AH, Koenig J, Huang H, Pyrski M, Millet Q, Lolignier S, et al. Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene-targeted mice. Embo J. 2018;37:427–45. https://doi.org/10.15252/embj.201796692
Sumi T, Imasaki T, Aoki M, Sakai N, Nitta E, Shirouzu M, et al. Structural insights into the altering function of CRMP2 by phosphorylation. Cell Struct Funct. 2018;43:15–23. https://doi.org/10.1247/csf.17025
Wilson SM, Ki Yeon S, Yang XF, Park KD, Khanna R. Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ss and CDK5 following traumatic brain injury. Front Cell Neurosci. 2014;8:135 https://doi.org/10.3389/fncel.2014.00135
Brittain JM, Wang Y, Eruvwetere O, Khanna R. Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2. FEBS Lett. 2012;586:3813–8. https://doi.org/10.1016/j.febslet.2012.09.022
Bolash RB, Niazi T, Kumari M, Azer G, Mekhail N. Efficacy of a targeted drug delivery on-demand bolus option for chronic pain. Pain Pract. 2018;18:305–13. https://doi.org/10.1111/papr.12602
Hayek SM, Sweet JA, Miller JP, Sayegh RR. Successful management of corneal neuropathic pain with intrathecal targeted drug delivery. Pain Med. 2016;17:1302–7. https://doi.org/10.1093/pm/pnv058
Berta T, Qadri Y, Tan PH, Ji RR. Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain. Expert Opin Ther Targets. 2017;21:695–703. https://doi.org/10.1080/14728222.2017.1328057
Guha D, Shamji MF. The dorsal root Ganglion in the pathogenesis of chronic neuropathic pain. Neurosurgery. 2016;63:118–26. https://doi.org/10.1227/NEU.0000000000001255
Hogan QH. Labat lecture: the primary sensory neuron: where it is, what it does, and why it matters. Reg Anesth Pain Med. 2010;35:306–11. https://doi.org/10.1097/AAP.0b013e3181d2375e
Terashima T, Ogawa N, Nakae Y, Sato T, Katagi M, Okano J, et al. Gene therapy for neuropathic pain through siRNA-IRF5 gene delivery with homing peptides to microglia. Mol Ther Nucleic Acids. 2018;11:203–15. https://doi.org/10.1016/j.omtn.2018.02.007
Zheng Y, Sethi R, Mangala LS, Taylor C, Goldsmith J, Wang M, et al. Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation. Nat Commun. 2018;9:476 https://doi.org/10.1038/s41467-017-02811-7
Fischer G, Kostic S, Nakai H, Park F, Sapunar D, Yu H, et al. Direct injection into the dorsal root ganglion: technical, behavioral, and histological observations. J Neurosci Methods. 2011;199:43–55.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63.
Wu HE, Gemes G, Zoga V, Kawano T, Hogan QH. Learned avoidance from noxious mechanical simulation but not threshold semmes weinstein filament stimulation after nerve injury in rats. J Pain. 2010;11:280–6. https://doi.org/10.1016/j.jpain.2009.07.011
Yu H, Fischer G, Jia G, Reiser J, Park F, Hogan QH. Lentiviral gene transfer into the dorsal root ganglion of adult rats. Mol Pain. 2011;7:63.
Liu Z, Wang F, Fischer G, Hogan QH & Yu H. Peripheral nerve injury induces loss of nociceptive neuron-specific Galphai-interacting protein in neuropathic pain rat. Mol Pain. https://doi.org/10.1177/1744806916646380 (2016).
Ramer MS, Duraisingam I, Priestley JV, McMahon SB. Two-tiered inhibition of axon regeneration at the dorsal root entry zone. J Neurosci. 2001;21:2651–60.
Xiang H, Xu H, Fan F, Shin SM, Hogan QH & Yu H. Glial fibrillary acidic protein promoter determines transgene expression in satellite glial cells following intraganglionic adeno-associated virus delivery in adult rats. J Neurosci Res. https://doi.org/10.1002/jnr.24183 (2017).
This research was supported by a grant from the Department of Veterans Affairs Rehabilitation Research and Development I01RX001940 (to Q. Hogan). R. Khanna is supported by grants from National Institutes of Health Awards (1R01NS098772 and 1R01DA042852). H. Xiang was a recipient of National Natural Science Foundation of China (81802190, 81772412). Y. Cai was a recipient of Chinese Scholarship Council.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Yu, H., Shin, S., Xiang, H. et al. AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain. Gene Ther 26, 308–323 (2019). https://doi.org/10.1038/s41434-019-0082-7
This article is cited by
Gene Therapy (2022)
Molecular Neurobiology (2021)
Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice
Molecular Brain (2020)