Functional Interactions of Fibrillar and Oligomeric Amyloid-β with Alpha7 Nicotinic Receptors in Alzheimer's Disease
Abstract
Amyloid-β (Aβ) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that Aβ binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and Aβ pathogenesis. However, it is not yet known how the different Aβ assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar Aβ(1-40) is prevented through an α7 nAChR-dependent mechanism. The α7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [³H]PIB to fibrillar Aβ in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of Aβ with α7 nAChRs and prevent the formation of Aβ/α7 nAChR complexes. This interaction was confirmed in binding assays with [¹²⁵I]Aβ(1-40) and α7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of Aβ fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca(2+)](i) levels. Oligomeric, but not fibrillar Aβ(1-40), increased [Ca(2+)](i) in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar Aβ exerts neurotoxic effects mediated partly through a blockade of α7 nAChRs, whilst oligomeric Aβ may act as a ligand activating α7 nAChRs, thereby stimulating downstream signaling pathways.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Oligomeric Aβ particles suppress LTP and enhance LTD through interactions with synaptic proteins such as mGluRs and potentially α7-nAChR.
“Oligomeric A particles suppress LTP and enhance long-term depression (LTD) through interactions with synaptic proteins (and reviewed in Refs.31 and 55), such as metabotropic glutamate receptors (mGluRs) as well as potentially the Ca 2ϩ -permeable ␣7-nicotinic acetylcholine receptor (␣7-nAChR) (reviewed in Refs.56 and 57).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [56]
Cites
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B
Klunk, W. E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D. P., Bergström, M., Savitcheva, I., Huang, G., Estrada, S., et al. (2004) · Annals of Neurology · doi:10.1002/ana.20009 · Cited by 4,496 · see citing works
Self-citationWalsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Aβ Oligomers – a decade of discovery
Walsh, D. M., & Selkoe, D. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04426.x · Cited by 1,938 · see citing works
Regulation of NMDA receptor trafficking by amyloid-β
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., Nairn, A. C., Salter, M. W., Lombroso, P. J., Gouras, G. K., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1503 · Cited by 1,561 · see citing works
Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer’s Disease
Busche, M. A., Eichhoff, G., Adelsberger, H., Abramowski, D., Wiederhold, K.-H., Haass, C., Staufenbiel, M., Konnerth, A., & Garaschuk, O. (2008) · Science · doi:10.1126/science.1162844 · Cited by 1,125 · see citing works
Demuro, A., Mina, E. W., Kayed, R., Milton, S. C. F., Parker, I., & Glabe, C. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500997200 · Cited by 1,038 · see citing works
In vitro characterization of conditions for amyloid-β peptide oligomerization and fibrillogenesis
Stine, W. B., Dahlgren, K. N., Krafft, G. A., & LaDu, M. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210207200 · Cited by 1,015 · see citing works
Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
Coe, J. W., Brooks, P. R., Vetelino, M. G., Wirtz, M. C., Arnold, E. P., Huang, J., Sands, S. B., Davis, T. I., Lebel, L. A., Fox, C. B., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050069n · Cited by 930 · see citing works
Neuronal nicotinic receptors in the human brain
Paterson, D., & Nordberg, A. K. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(99)00045-3 · Cited by 782 · see citing works
Self-citationStructure–neurotoxicity relationships of amyloid β-protein oligomers
Ono, K., Condron, M. M., & Teplow, D. B. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905127106 · Cited by 774 · see citing works
De Felice, F. G., Vieira, M. N. N., Bomfim, T. R., Decker, H., Velasco, P. T., Lambert, M. P., Viola, K. L., Zhao, W.-Q., Ferreira, S. T., & Klein, W. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809158106 · Cited by 657 · cited 1× · see citing works
“In addition to the different cell surface receptors defined as putative targets for oligomeric A , modulation of signaling cascades regulating these receptors may also be important for attenuating A toxicity and preventing A -mediated loss of receptors [38].”
Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors
Mihalak, K. B., Carroll, F. I., & Luetje, C. W. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.025130 · Cited by 558 · see citing works
PET imaging of amyloid in Alzheimer's disease
Nordberg, A. K. (2004) · The Lancet Neurology · doi:10.1016/s1474-4422(04)00853-1 · Cited by 462 · see citing works
Self-citationβ-Amyloid Monomers Are Neuroprotective
Giuffrida, M. L., Caraci, F., Pignataro, B., Cataldo, S., De Bona, P., Bruno, V., Molinaro, G., Pappalardo, G., Messina, A., Palmigiano, A., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1736-09.2009 · Cited by 421 · see citing works
β-Amyloid peptide blocks the response of α7-containing nicotinic receptors on hippocampal neurons
Liu, Q.-S., Kawai, H., & Berg, D. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.081553598 · Cited by 316 · see citing works
Nicotinic receptor stimulation protects neurons against β‐amyloid toxicity
Kihara, T., Shimohama, S., Sawada, H., Kimura, J., Kume, T., Kochiyama, H., Maeda, T., & Akaike, A. (1997) · Annals of Neurology · doi:10.1002/ana.410420205 · Cited by 315 · see citing works
Monoclonal antibodies that target pathological assemblies of Aβ
Lambert, M. P., Velasco, P. T., Chang, L., Viola, K. L., Fernandez, S., Lacor, P. N., Khuon, D., Gong, Y., Bigio, E. H., Shaw, P., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04157.x · Cited by 314 · see citing works
β-Amyloid 1–42 Peptide Directly Modulates Nicotinic Receptors in the Rat Hippocampal Slice
Pettit, D. L., Shao, Z., & Yakel, J. L. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-01-j0003.2001 · Cited by 291 · see citing works
β-Amyloid Peptide Activates α7 Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes
Dineley, K. T., Bell, K. A., Bui, D., & Sweatt, J. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200066200 · Cited by 241 · see citing works
Nicotine Inhibits Amyloid Formation by the β-Peptide
Salomon, A. R., Marcinowski, K. J., Friedland, R. P., & Zagorski, M. G. (1996) · Biochemistry · doi:10.1021/bi9617264 · Cited by 220 · see citing works
β-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex
Dougherty, J. J., Wu, J., & Nichols, R. A. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-17-06740.2003 · Cited by 213 · see citing works
Picciotto, M. R. (2007) · Frontiers in bioscience · doi:10.2741/2695 · Cited by 212 · see citing works
The Toxicity of the Alzheimer's β-Amyloid Peptide Correlates with a Distinct Fiber Morphology
Seilheimer, B., Bohrmann, B., Bondolfi, L., Müller, F., Stüber, D., & Döbeli, H. (1997) · Journal of Structural Biology · doi:10.1006/jsbi.1997.3859 · Cited by 207 · see citing works
Maggio, J. E., Stimson, E. R., Ghilardi, J. R., Allen, C. J., Dahl, C. E., Whitcomb, D. C., Vigna, S. R., Vinters, H. V., Labenski, M. E., & Mantyh, P. W. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5462 · Cited by 194 · see citing works
Lukas, R. J., Norman, S. A., & Lucero, L. M. (1993) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.1993.1001 · Cited by 192 · see citing works
Liu, Q., Huang, Y., Xue, F., Simard, A. R., DeChon, J., Li, G., Zhang, J., Lucero, L. M., Wang, M., Sierks, M. R., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3952-08.2009 · Cited by 182 · see citing works
Dual effects of nicotine on oxidative stress and neuroprotection in PC12 cells
Guan, Z. (2003) · Neurochemistry International · doi:10.1016/s0197-0186(03)00009-3 · Cited by 175 · see citing works
Yu, W., Guan, Z.-Z., Bogdanović, N., & Nordberg, A. K. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2004.12.015 · Cited by 153 · see citing works
Self-citationKadir, A., Almkvist, O., Wall, A. E., Långström, B., & Nordberg, A. K. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0447-7 · Cited by 146 · see citing works
Self-citationLiu, Q., & Zhao, B. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705653 · Cited by 130 · see citing works
Wang, H.-Y., Stucky, A., Liu, J., Shen, C., Trocmé, C., & Morain, P. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.6088-08.2009 · Cited by 102 · see citing works
Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron emission tomography
Klunk, W. E., Engler, H., Nordberg, A., Bacskai, B. J., Wang, Y., Price, J. C., Bergström, M., Hyman, B. T., Långström, B., & Mathis, C. A. (2003) · Neuroimaging Clinics of North America · doi:10.1016/s1052-5149(03)00092-3 · Cited by 96 · see citing works
Self-citationMarutle, A., Berglund, U. W., Bogdanović, N., & Nordberg, A. K. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00558-7 · Cited by 96 · see citing works
Self-citationRamsden, M., Henderson, Z., & Pearson, H. A. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03547-3 · Cited by 87 · see citing works
PET studies and cholinergic therapy in Alzheimer's disease.
Nordberg, A. K. (1999) · PubMed · Cited by 76 · see citing works
Self-citationLee, D. H. S., & Wang, H.-Y. (2003) · Journal of Neurobiology · doi:10.1002/neu.10203 · Cited by 67 · see citing works
β-Amyloid Peptide Activates Non-α7 Nicotinic Acetylcholine Receptors in Rat Basal Forebrain Neurons
Fu, W., & Jhamandas, J. H. (2003) · Journal of Neurophysiology · doi:10.1152/jn.00616.2003 · Cited by 59 · see citing works
Guan, Z. Z., Miao, H., Tian, J., Unger, C., Nordberg, A. K., & Zhang, X. (2001) · Journal of Neural Transmission · doi:10.1007/s007020100017 · Cited by 56 · see citing works
Self-citationWang, H.-Y., Bakshi, K. P., Shen, C., Frankfurt, M., Trocmé, C., & Morain, P. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.09.031 · Cited by 50 · see citing works
JN403, in vitro characterization of a novel nicotinic acetylcholine receptor α7 selective agonist
Feuerbach, D., Nozulak, J., Lingenhoehl, K., McAllister, K. H., & Hoyer, D. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.01.045 · Cited by 43 · see citing works
Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex
Leung, E., Guo, L., Bu, J., Maloof, M. E., Khoury, J. B. E., & Geula, C. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.02.025 · Cited by 40 · see citing works
Bezprozvanny, I. B. (2009) · Science Signaling · doi:10.1126/scisignal.263pe16 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses
Wasser, C. R., & Herz, J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.766782 · Cited by 111 · see citing works
Amyloid-β oligomers in cellular models of Alzheimer’s disease
Fontana, I. C., Zimmer, A. R., Rocha, A. S., Gosmann, G., Souza, D. O., Lourenco, M. V., Ferreira, S. T., & Zimmer, E. R. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15030 · Cited by 115 · see citing works
The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease
Fontana, I. C., Kumar, A., & Nordberg, A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00792-4 · Cited by 86 · see citing works
Self-citationMarutle, A., Gillberg, P.-G., Bergfors, A., Yu, W., Ni, R., Nennesmo, I., Voytenko, L., & Nordberg, A. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-90 · Cited by 70 · see citing works
Self-citationReelin links Apolipoprotein E4, Tau, and Amyloid‐β in Alzheimer’s disease
Yi, L. X., Zeng, L., Wang, Q., Tan, E. K., & Zhou, Z. D. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102339 · Cited by 41 · see citing works
Beta-amyloid oligomers: recent developments
Borutaite, V., Morkuniene, R., & Valincius, G. (2011) · bmc · doi:10.1515/bmc.2011.019 · Cited by 9 · see citing works
- Authors
- Lilja, A. M., Porras, O., Storelli, E., Nordberg, A., & Marutle, A.
- Affiliations
- Karolinska University Hospital (SE)
- Corresponding author
- Marutle, Amelia
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2011-02-26
- Volume
- 23
- Issue
- 2
- Pages
- 335-347
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2152703476
- Cited by
- 57
- References
- 47
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 2 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 3 · 2013: 11 · 2012: 4
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- Universität Basel
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, alpha7 nicotinic acetylcholine receptor
- MeSH terms
- Varenicline, Aged, Alzheimer Disease, Analysis of Variance, Animals, Benzazepines, Carbamates, Cells, Cultured, Frontal Lobe, Humans, Neurons, Quinoxalines, Quinuclidines, Receptors, Nicotinic, Amyloid beta-Peptides, PC12 Cells, Nicotinic Agonists, Cell Line, Tumor, Rats, alpha7 Nicotinic Acetylcholine Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
