Astrocytic α7 Nicotinic Receptor Activation Inhibits Amyloid-β Aggregation by Upregulating Endogenous αB-crystallin through the PI3K/Akt Signaling Pathway

Author(s): Zhenkui Ren, Mei Yang, Zhizhong Guan, Wenfeng Yu*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 1 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Background: β-amyloid (Aβ) aggregation plays an important role in the pathogenesis of Alzheimer’s disease (AD), and astrocytes can significantly inhibit Aβ aggregation. Astrocytic α7 Neuronal Nicotinic Acetylcholine Receptor (nAChR) upregulation detected in the AD brains is closely associated with Aβ deposits. However, the relationships between the astrocytic α7 nAChRs and Aβ aggregation remain unclear.

Methods: The Aβ oligomers levels in astrocytic cell lysates and culture medium were measured after treatment with nicotine or co-treatment with a Phosphatidylinositol 3-Kinase (PI3K)-protein kinase B (Akt) inhibitor. The level of αB-Crystallin (Cryab) in astrocytes treated with nicotine for different times or co-treated with α7 nAChR antagonists as well as co-incubated with a PI3K or mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was determined by western blotting.

Results: In this study, nicotine pre-treatment in primary astrocytes markedly inhibited Aβ aggregation and upregulated endogenous astrocytic Cryab, while the nicotine-mediated neuroprotective effect was reversed by pre-treatment with a selective α7 nAChR antagonist. Furthermore, this neuroprotection against Aβ aggregation was suppressed by LY294002, a PI3K inhibitor. Pre-treatment with nicotine significantly increased the levels of phosphorylated Akt, an effector of PI3K in astrocytes.

Conclusion: α7 nAChR activation and PI3K/Akt signaling transduction contributed to nicotinemediated neuroprotection against Aβ aggregation by modulating endogenous astrocytic Cryab.

Keywords: Alzheimer's disease, β -amyloid aggregation, α7 neuronal nicotinic acetylcholine receptors, PI3K/Akt signaling pathway, αB-crystallin, dementia.

Braak H, Braak E. Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18(4)(Suppl.): S85-8. (1997).
Robinson S, Bishop G. The search for an amyloid solution Science 298(5595): 962-64 (2002)author reply 962-4.
Cole T, Burkhardt D, Ghosh P, Ryan M, Taylor T. Effects of spinal fusion on the proteoglycans of the canine intervertebral disc. J Orthop Res 3(3): 277-91. (1985).
Ariga T, McDonald M, Yu R. Role of ganglioside metabolism in the pathogenesis of Alzheimer’s disease-a review. J Lipid Res 49(6): 1157-75. (2008).
Hardy J, Higgins G. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054): 184-5. (1992).
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300(5618): 486-9. (2003).
Yamin G, Ono K, Inayathullah M, Teplow DB. Amyloid beta-protein assembly as a therapeutic target of Alzheimer’s disease. Curr Pharm Des 14(30): 3231-46. (2008).
Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman AB, Aschner M. Role of astrocytes in brain function and disease. Toxicol Pathol 39(1): 115-23. (2011).
Nielsen H, Veerhuis R, Holmqvist B, Janciauskiene S. Binding and uptake of A beta1-42 by primary human astrocytes in vitro. Glia 57(9): 978-88. (2009).
Pihlaja R, Koistinaho J, Malm T, Sikkilä H, Vainio S, Koistinaho M. Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer’s disease. Glia 56(2): 154-63. (2008).
Parri H, Hernandez C, Dineley K. Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol 82(8): 931-42. (2011).
Yu W, Guan ZZ, Bogdanovic N, Nordberg A. High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer’s disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Exp Neurol 192(1): 215-25. (2005).
Yu W, Mechawar N, Krantic S, Chabot J-G, Quirion R. Upregulation of astrocytic α7 nicotinic receptors in Alzheimer’s disease brain- possible relevant to amyloid pathology. Mol Neurodegen 7(S1): 1-2. (2012).
Bhat R, Steinman L. Innate and adaptive autoimmunity directed to the central nervous system. Neuron 64(1): 123-32. (2009).
Ousman S, Tomooka BH, van Noort JM, Wawrousek EF, O’Connor KC, Hafler DA, et al. Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 448(7152): 474-9. (2007).
Shammas S, Waudby AC, Wang S, Buell AK, Knowles TPJ, Ecroyd H, et al. Binding of the molecular chaperone αB-crystallin to Aβ amyloid fibrils inhibits fibril elongation. Biophys J 101(7): 1681-9. (2011).
Wilhelmus M, Boelens WC, Otte-Höller I, Kamps B, de Waal RM, Verbeek MM, et al. Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity. Brain Res 1089(1): 67-78. (2006).
Raman B, Ban T, Sakai M, Pasta SY, Ramakrishna T, Naiki H, et al. AlphaB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid beta-peptide and beta2-microglobulin. Biochem J 392(Pt 3): 573-81. (2005).
McCarthy K, de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85(3): 890-902. (1980).
Klein W. Abeta toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int 41(5): 345-52. (2002).
Rönicke R, Mikhaylova M, Rönicke S, Meinhardt J, Schröder UH, Fändrich M, et al. Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiol Aging 32(12): 2219-28. (2011).
Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, et al. Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res 792(2): 331-4. (1998).
Steiner R, Heath C, Picciotto M. Nicotine-induced phosphorylation of ERK in mouse primary cortical neurons: evidence for involvement of glutamatergic signaling and CaMKII. J Neurochem 103(2): 666-78. (2007).
Reix S, Mechawar N, Susin SA, Quirion R, Krantic S. Expression of cortical and hippocampal apoptosis-inducing factor (AIF) in aging and Alzheimer’s disease. Neurobiol Aging 28(3): 351-6. (2007).
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284): 99-102. (1996).
Hellström-Lindahl E, Court J, Keverne J, Svedberg M, Lee M, Marutle A, et al. Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. Eur J Neurosci 19(10): 2703-10. (2004).
Yu W, Mechawar N, Krantic S, Quirion R. α7 Nicotinic receptor activation reduces β-amyloid-induced apoptosis by inhibiting caspase-independent death through phosphatidylinositol 3-kinase signaling. J Neurochem 119(4): 848-58. (2011).
Wang D, Meng Q, Leech CA, Yepuri N, Zhang L, Holz GG, et al. α7 Nicotinic acetylcholine receptor regulates the function and viability of L cells. Endocrinology 159(9): 3132-42. (2018).
Wan C, Wu M, Zhang S, Chen Y, Lu C. α7nAChR-mediated recruitment of PP1γ promotes TRAF6/NF-κB cascade to facilitate the progression of Hepatocellular Carcinoma. Mol Carcinog 57(11): 1626-39. (2018).
Chen T, Wang Y, Zhang T, Zhang B, Chen L, Zhao L, et al. Simvastatin enhances activity and trafficking of α7 nicotinic acetylcholine receptor in hippocampal neurons through pkc and camkii signaling pathways. Front Pharmacol 9: 362. (2018).
Vivekanandarajah A, Chan YL, Chen H, Machaalani R. Prenatal cigarette smoke exposure effects on apoptotic and nicotinic acetylcholine receptor expression in the infant mouse brainstem. Neurotoxicology 53-63. (2016).
Lopes F, Graepel R, Reyes JL, Wang A, Petri B, McDougall JJ, et al. Involvement of mast cells in α7 nicotinic receptor agonist exacerbation of freund’s complete adjuvant-induced monoarthritis in mice. Null 68(2): 542-52. (2016).
Di Cesare Mannelli L, Tenci B, Zanardelli M, Failli P, Ghelardini C. α7 Nicotinic receptor promotes the neuroprotective functions of astrocytes against oxaliplatin neurotoxicity. Neural Plast 2015: 396908. (2015).
Liu Q, Xie X, Emadi S, Sierks MR, Wu J. A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity. Neuropharmacology 97: 457-63. (2015).
Gendron R, Plamondon P, Grenier D. Binding of pro-matrix metalloproteinase 9 by Fusobacterium nucleatum subsp. nucleatum as a mechanism to promote the invasion of a reconstituted basement membrane. Infect Immun 72(10): 6160-53. (2004).
Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF. Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer’s disease. J Neurosci 29(27): 8805-15. (2009).
Zeng H, Zhang Y, Peng L, Shao H, Menon NK, Yang J, et al. Nicotine and amyloid formation. Biol Psychiatry 49(3): 248-57. (2001).
Safronova V, Vulfius CA, Shelukhina IV, Mal’tseva VN, Berezhnov AV, Fedotova EI, et al. Nicotinic receptor involvement in regulation of functions of mouse neutrophils from inflammatory site. Immunobiology 221(7): 761-72. (2016).
Hu J, Zhu C, Liu Y, Wang F, Huang Z, Fan W, et al. Dynamic alterations of gene expression of nicotinic acetylcholine receptor α7, α4 and β2 subunits in an acute MPTP-lesioned mouse model. Neurosci Lett 494(3): 232-6. (2011).
Akaike A, Takada-Takatori Y, Kume T, Izumi Y. Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of alpha4 and alpha7 receptors in neuroprotection. J Mol Neurosci 40(1-2): 211-6. (2010).
Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, et al. α7 Nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block a β-amyloid-induced neurotoxicity. J Biol Chem 276(17): 13541-6. (2001).
Qi Y, Dou DQ, Jiang H, Zhang BB, Qin WY, Kang K, et al. Arctigenin attenuates learning and memory deficits through pi3k/akt/gsk-3β pathway reducing tau hyperphosphorylation in Aβ- induced AD mice. Planta Medica 83(01/02): 51-56 (2017).
Bitner RS, Bunnelle WH, Decker MW, Drescher KU, Kohlhaas KL, Markosyan S, et al. In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer’s disease. J Pharmacol Exp Ther 334(3): 875. (2010).

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [39 - 48]
Pages: 10
DOI: 10.2174/1567205015666181022093359
Price: $58

Article Metrics

PDF: 32