Memory recovery through gene therapy with a single chain antibody fragment selective for Aβ oligomers in a model of Alzheimer’s disease in rats

Authors

  • Natalia-Claudia Colettis Laboratory of Neuroplasticity and Neurotoxins (LaN&N), Facultad de Medicina, Instituto de Biología Celular y Neurociencia (IBCN) “Prof. Eduardo De Robertis” (Universidad de Buenos Aires – CONICET), Buenos Aires, Argentina.
  • Maria-Victoria Oberholzer Instituto de Biología Celular y Neurociencia (IBCN) “Prof. Eduardo De Robertis” (Universidad de Buenos Aires – CONICET)
  • Magali Cercato Laboratory of Neuroplasticity and Neurotoxins (LaN&N), Facultad de Medicina, Instituto de Biología Celular y Neurociencia (IBCN) “Prof. Eduardo De Robertis” (Universidad de Buenos Aires – CONICET), Buenos Aires, Argentina.
  • Martin Habif Laboratory of Neuroplasticity and Neurotoxins (LaN&N), Facultad de Medicina, Instituto de Biología Celular y Neurociencia (IBCN) “Prof. Eduardo De Robertis” (Universidad de Buenos Aires – CONICET), Buenos Aires, Argentina
  • Maria-Clara Selles Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
  • Daniela Salas Laboratory of Neuroplasticity and Neurotoxins (LaN&N), Facultad de Medicina, Instituto de Biología Celular y Neurociencia (IBCN) “Prof. Eduardo De Robertis” (Universidad de Buenos Aires – CONICET)
  • Adriano Sebollela Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, Brazil
  • William-L. Klein Northwestern University: Evanston, IL, US
  • Alberto-L. Epstein EG 427, Hôpital Cochin 29, rue du Faubourg Saint Jacques. 75014 – Paris, France
  • Anna Salvetti CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
  • Sergio-T. Ferreira Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil
  • Diana Jerusalinsky Instituto de Biología Celular y Neurociencia (IBCN) “Prof. Eduardo De Robertis” (Universidad de Buenos Aires – CONICET)

DOI:

https://doi.org/10.17981/JACN.4.1.2023.2

Keywords:

LTM, Alzheimer’s Disease, gene therapy, scFv, single chain antibody fragment, Aβ oligomers

Abstract

Strong evidence supports the hypothesis that synapse damage and memory impairment in early Alzheimer disease (AD) might be due to synaptic failure caused by amyloid beta oligomers (AβOs). We demonstrated the preclinical efficacy of a single-chain variable-fragment (scFv) antibody NUsc1 that selectively targets a subpopulation of AβOs; NUsc1 prevented AβO-induced inhibition of long-term potentiation in hippocampal slices and short-term memory impairment in mice. Since specific targeting of AβOs by NUsc1 may be a substantial improvement in target engagement and efficacy for AD therapy, we developed an adeno-associated virus (AAV) vector to drive neuronal expression of NUsc1 within the brain. AAV-NUsc1 rescued short-term memory (STM) for objects and congeners interaction in mice AD models. Purpose: In heterozygous McGill-R-Thy1-APP transgenic (Tg+/–) rat model of AD, progressive amyloid pathology is accompanied by cognitive impairment involving long-term memory (LTM) decline. LTM in a novel-object-recognition (NOR) task was impaired in 4-month-old (Tg+/–) male rats, suggesting that they are unable to form/evoke such discriminative memories. Hence, we investigated if AAV-NUsc1 treatment could rescued this memory. Methods: 10-12 weeks-old either Tg or wild type male rats were i.c.v. infused with AAV-NUsc1. Two months later, short-term exploratory behavior, habituation to an open field (OF), object discrimination and LTM for objects were assessed. Results: AAV-NUsc1 treated Tg rats were able to successfully perform the task 24 h after training, denoting recovery of LT discrimination capacity and LTM formation. Wild type rats successfully performed the task either treated or not with AAV-NUsc1. Also, exploration and short-term habituation to an open field was preserved in Tg+/– rats either treated or not. Conclusions: Our present and previous results suggest that AAV-NUsc1 represents a significant advance in gene therapy, supporting the feasibility of immunotherapy using viral vector-mediated NUsc1 gene delivery as a potential therapeutic approach in AD.

Downloads

Download data is not yet available.

Author Biography

Maria-Clara Selles, Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil

Also: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil. 

References

Ahmad, Z.; Yeap, S.; Ali, A.; Ho, W.; Alitheen, N. & Hamid, M. (2012). ScFv antibody: Principles and clinical application. Clinical and Developmental Immunology, 1–16.

https://doi.org/10.1155/2012/980250

Akkerman, S.; Blokland, A.; Reneerkens, O.; Van Goethem, N.; Bollen, E.; Gijselaers, H.; Lieben, C.; Steinbusch, H. & Prickaerts, J. (2012). Object recognition testing: Methodological considerations on exploration and discrimination measures. Behavioural Brain Research, 232(2), 335–347.

https://doi.org/10.1016/J.BBR.2012.03.022

Chabrier, M.; Cheng, D.; Castello, N.; Green, K. & LaFerla, F. (2014). Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiology of Disease, 64, 107–117.

https://doi.org/10.1016/j.nbd.2014.01.007

Do Carmo, S. & Cuello, A. (2013). Modeling Alzheimer’s disease in transgenic rats. Molecular Neurodegeneration, 8(1), 1–11.

https://doi.org/10.1186/1750-1326-8-37

Dunbar, C.; High, K.; Joung, J.; Kohn, D.; Ozawa, K. & Sadelain, M. (2018). Gene therapy comes of age. Science, 359(6372), 1–10.

https://doi.org/10.1126/SCIENCE.AAN4672

España, J.; Giménez-Llort, L.; Valero, J.; Miñano, A.; Rábano, A.; Rodriguez-Alvarez, J.; LaFerla, F. & Saura, C. A. (2010). Intraneuronal β-Amyloid Accumulation in the Amygdala Enhances Fear and Anxiety in Alzheimer’s Disease Transgenic Mice. Biological Psychiatry, 67(6), 513–521.

https://doi.org/10.1016/j.biopsych.2009.06.015

Ferreira, S. & Klein, W. (2011). The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiology of Learning and Memory, 96(4), 529–543.

https://doi.org/10.1016/J.NLM.2011.08.003

Ferrer, I.; Rovira, M.; Sanchez, M.; Rey, M. & Costa-Jussá, F. (2004). Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer’s Disease. Brain Pathology, 14(1), 11–20.

https://doi.org/10.1111/j.1750-3639.2004.tb00493.x

Fischell, J. & Fishman, P. (2021). A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases. Frontiers in Neuroscience, 15, 1–20.

https://doi.org/10.3389/fnins.2021.747726

Fukumoto, H.; Tokuda, T.; Kasai, T.; Ishigami, N.; Hidaka, H.; Kondo, M.; Allsop, D. & Nakagawa, M. (2010). High-molecular-weight β-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. The FASEB Journal, 24(8), 2716–2726.

https://doi.org/10.1096/FJ.09-150359

Fuller, J.; Stavenhagen, J. & Teeling, J. (2014). New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer’s Disease. Frontiers in Neuroscience, 8, 1–10.

https://doi.org/10.3389/FNINS.2014.00235

Galeano, P.; Martino, P.; Do Carmo, S.; Blanco, E.; Rotondaro, C.; Capani, F.; C­astaño, E.; Cuello, A. & Morelli, L. (2014). Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer’s disease. Frontiers in Behavioral Neuroscience, 8, 1–15.

https://doi.org/10.3389/fnbeh.2014.00321

Georganopoulou, D.; Chang, L.; Nam, J.; Thaxton, C.; Mufson, E.; Klein, W. & M­irkin, C. (2005). Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proceedings of the National Academy of Sciences, 102(7), 2273–2276.

https://doi.org/10.1073/pnas.0409336102

Gong, Y.; Chang, L.; Viola, K.; Lacor, P.; Lambert, M.; Finch, C.; Krafft, G. & Klein, W. (2003). Alzheimer’s disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proceedings of the National Academy of Sciences, 100(18), 10417–10422.

https://doi.org/10.1073/PNAS.1834302100

Habif, M.; Do Carmo, S.; Báez, M.; Colettis, N.; Cercato, M.; Salas, D.; Acutain, M.; Sister, C.; Berkowicz, V.; Canal, M.; González, T.; Cuello, A. & Jerusalinsky, D. (2021). Early Long-Term Memory Impairment and Changes in the Expression of Synaptic Plasticity-Associated Genes, in the McGill-R-Thy1-APP Rat Model of Alzheimer’s-Like Brain Amyloidosis. Frontiers in Aging Neuroscience, 12, 1–18.

https://doi.org/10.3389/fnagi.2020.585873

Holliger, P. & Hudson, P. (2005). Engineered antibody fragments and the rise of single domains. Nature Biotechnology, 23(9), 1126–1136.

https://doi.org/10.1038/nbt1142

Huang, L.; Su, X. & Federoff, H. (2013). Single-Chain Fragment Variable Passive Immunotherapies for Neurodegenerative Diseases. International Journal of Molecular Sciences, 14(9), 19109–19127.

https://doi.org/10.3390/IJMS140919109

Iulita, M.; Allard, S.; Richter, L.; Munter., L.; Ducatenzeiler, A.; Weise, C.; Do C­armo, S.; Klein, W.; Multhaup, G. & Cuello, A. (2014). Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathologica Communications, 2, 1–17.

https://doi.org/10.1186/2051-5960-2-61

Larson, M. & Lesné, S. (2012). Soluble Aβ oligomer production and toxicity. Journal of Neurochemistry, 120(SUPPL. 1), 125–139.

https://doi.org/10.1111/j.1471-4159.2011.07478.x

Leon, W.; Canneva, F.; Partridge, V.; Allard, S.; Ferretti, M.; DeWilde, A.; Vercautere­n, F.; Atifeh, R.; Ducatenzeiler, A.; Klein, W.; Szyf, M.; Alhonen, L. & Cuello, A. (2010). A Novel Transgenic Rat Model with a Full Alzheimer’s-Like Amyloid Pathology Displays Pre-Plaque Intracellular Amyloid-β-Associated Cognitive Impairment. Journal of Alzheimer’s Disease, 20(1), 113–126.

https://doi.org/10.3233/JAD-2010-1349

Monnier, P.; Vigouroux, R. & Tassew, N. (2013). In Vivo Applications of Single Chain Fv (Variable Domain) (scFv) Fragments. Antibodies, 2(2), 193–208.

https://doi.org/10.3390/antib2020193

Motulsky, H. & Beutler, E. B. (1989). GraphPad Prism (version 8.0.2) [Software]. GraphPad Software, Inc.

https://www.graphpad.com/

Mucke, L. & Selkoe, D. (2012). Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harbor Perspectives in Medicine, 2(7), 1–18.

https://doi.org/10.1101/cshperspect.a006338

Nicoll, J.; Wilkinson, D.; Holmes, C.; Steart, P.; Markham, H. & Weller, R. (2003). Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nature Medicine, 9(4), 448–452.

https://doi.org/10.1038/nm840

Orgogozo, J.-M.; Gilman, S.; Dartigues, J.-F.; Laurent, B.; Puel, M.; Kirby, L.; Jouann­y, P.; Dubois, B.; Eisner, L.; Flitman, S.; Michel, B.; Boada, M.; Frank, A. & Hock, C. (2003). Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology, 61(1), 46–54.

https://doi.org/10.1212/01.WNL.0000073623.84147.A8

Paxinos, G. & Watson, C. (2013). Rat brain in stereotaxic coordinates [7 ed.]. E­lsevier.

Pimentel, L.; Allard, S.; Do Carmo, S.; Weinreb, O.; Danik, M.; Hanzel, C.; Youdim, M. & Cuello, A. (2015). The Multi-Target Drug M30 Shows Pro-Cognitive and Anti-Inflammatory Effects in a Rat Model of Alzheimer’s Disease. Journal of Alzheimer’s Disease, 47(2), 373–383.

https://doi.org/10.3233/JAD-143126

Sebollela, A.; Cline, E.; Popova, I.; Luo, K.; Sun, X.; Ahn, J.; Barcelos, M.; Bezerra, V.; Lira e Silva, N.; Patel, J.; Pinheiro, N.; Qin, L.; Kamel, J.; Weng, A.; D­iNunno, N.; Bebenek, A.; Velasco, P.; Viola, K.; Lacor, P.; Ferreira, S. & Klein, W. (2017). A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers. Journal of Neurochemistry, 142(6), 934–947.

https://doi.org/10.1111/JNC.14118

Selkoe, D. & Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Molecular Medicine, 8(6), 595–608.

https://doi.org/10.15252/EMMM.201606210

Selles, M.; Fortuna, J.; Cercato, M.; Santos, L.; Domett, L.; Bitencourt, A.; Carraro, M.; Souza, A.; Janickova, H.; Azevedo, C.; Campos, H.; De Souza, J.; Alves-Leon, S.; Prado, V.; Prado, M.; Epstein, A.; Salvetti, A.; Longo, B.; Arancio, O.; Klein, W.; Sebollela, A.; De Felice, F.; Jerusalinsky, D. & Ferreira, S. (2022). AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. Molecular Therapy, 31(2), 409–419.

https://doi.org/10.1016/j.ymthe.2022.11.002

Sevigny, J.; Chiao, P.; Bussière, T.; Weinreb, P.; Williams, L.; Maier, M.; Dunstan, R.; Salloway, S.; Chen, T.; Ling, Y.; O’Gorman, J.; Qian, F.; Arastu, M.; Li, M.; Chollate, S.; Brennan, M.; Quintero-Monzon, O.; Scannevin, R.; Arnold, H.; Engber, T.; Rhodes, K.; Ferrero, J.; Hang, Y.; Mikulskis, A.; Grimm, J.; Hock, C.; Nitsch, R. & Sandrock, A. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 537(7618), 50–56.

https://doi.org/10.1038/nature19323

Tomiyama, T.; Matsuyama, S.; Iso, H.; Umeda, T.; Takuma, H.; Ohnishi, K.; Ishibashi, K.; Teraoka, R.; Sakama, N.; Yamashita, T.; Nishitsuji, K.; Ito, K.; Shimada, H.; Lambert, M.; Klein, W. & Mori, H. (2010). A mouse model of amyloid β oligomers: Their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. Journal of Neuroscience, 30(14), 4845–4856.

https://doi.org/10.1523/JNEUROSCI.5825-09.2010

Tran, T.; Kim, S.; Gallo, C.; Amaya, M.; Kyees, J. & Narayanaswami, V. (2013). Biochemical and biophysical characterization of recombinant rat apolipoprotein E: Similarities to human apolipoprotein E3. Archives of Biochemistry and Biophysics, 529(1), 18–25.

https://doi.org/10.1016/j.abb.2012.10.007

Van Dyck, C.; Swanson, C.; Aisen, P.; Bateman, R.; Chen, C.; Gee, M.; Kanekiyo, M.; Li, D.; Reyderman, L.; Cohen, S.; Froelich, L.; Katayama, S.; Sabbagh, M.; Vellas, B.; Watson, D.; Dhadda, S.; Irizarry, M.; Kramer, L. & Iwatsubo, T. (2022). Lecanemab in Early Alzheimer’s Disease. The New England Journal of Medicine, 388(1), 9–21.

https://doi.org/10.1056/NEJMoa2212948

Velasco, P.; Heffern, M.; Sebollela, A.; Popova, I.; Lacor, P.; Lee, K.; Sun, X.; Tiano, B.; Viola, K.; Eckermann, A.; Meade, T. & Klein, W. (2012). Synapse-Binding Subpopulationsof Aβ OligomersSensitive to Peptide Assembly Blockers and scFv Antibodies. ACS Chemical Neuroscience, 3(11), 972–981.

https://doi.org/10.1021/cn300122k

Downloads

Published

2023-01-24

How to Cite

Colettis, N.-C., Oberholzer, M.-V., Cercato, M., Habif, M., Selles, M.-C. ., Salas, D., Sebollela, A. ., Klein, W.-L. ., Epstein, A.-L. ., Salvetti, A. ., Ferreira, S.-T., & Jerusalinsky, D. (2023). Memory recovery through gene therapy with a single chain antibody fragment selective for Aβ oligomers in a model of Alzheimer’s disease in rats. Journal of Applied Cognitive Neuroscience, 4(1), e00344688. https://doi.org/10.17981/JACN.4.1.2023.2

Issue

Vol. 4 No. 1 (2023): Journal of Applied Cognitive Neuroscience

Section

Original Article

License

Copyright (c) 2023 JOURNAL OF APPLIED COGNITIVE NEUROSCIENCE

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

You are free to:

  1. Share — copy and redistribute the material in any medium or format.
  2. The licensor cannot revoke these freedoms as long as you follow the license terms.

Under the following terms:

  1. Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
  2. NonCommercial — You may not use the material for commercial purposes.
  3. NoDerivatives — If you remix, transform, or build upon the material, you may not distribute the modified material.
  4. No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.