Abstract
Cerebral deposition of amyloid β-peptide (Aβ), a fundamental feature of Alzheimer’s disease (AD), damages the neurocytes and impairs the cognition functions and associative learning memory of AD patients. A series of novel 2-arylethenylquinoline derivatives were synthesized and evaluated in our previous study, which inhibited Aβ aggregation in vitro effectively at the concentration of 20 μmol/L and exhibited high antioxidant activity. In order to verify the capacity of anti-AD in vivo, the transgenic Caenorhabditis elegans (C. elegans) strain CL2355 expressing neural Aβ was employed as the AD model to investigate the neuroprotective activity of seven high-potential compounds (4a1, 4a2, 4b1, 4b2, 4c1, 4c2, 4c3) selected from those derivatives. Learning memory associated chemotaxis assay was performed to evaluate the neural repairment capacity. The underlying mechanism was investigated by mRNA analysis of Aβ gene and heat shock protein genes (hsp-16.1 and hsp-16.2) and Western blot of Aβ. Our data indicated that among seven tested compound, 4b1 and 4c2 reduced Aβ-induced stress, suppressed the expression of neural Aβ monomers and toxic oligomers, and recovered the damaged associative learning memory in C. elegans AD model. These findings further confirmed their potentials to become valuable agents for AD therapy.
Similar content being viewed by others
Abbreviations
- AD:
-
Alzheimer’s disease
- ANOVA:
-
Analysis of variance
- Aβ:
-
Amyloid beta-peptide
- C. elegans :
-
Caenorhabditis elegans
- CI:
-
Chemotactic index
- DMSO:
-
Dimethyl sulfoxide
- E. coli :
-
Escherichia coli
- hsp-16.1 :
-
Heat shock protein 16.1 gene
- hsp-16.2 :
-
Heat shock protein 16.2 gene
- L1 stage:
-
Larvae one stage
- NGM:
-
Nematode growth medium
- RT-qPCR:
-
Reverse transcription quantitative polymerase chain reaction
- SD:
-
Standard deviations
- snb-1 :
-
Synaptobrevin ortholog
- Trizol:
-
Total RNA Extractor
- YA stage:
-
Young adulthood stage
- *4a1, 4a2, 4b1, 4b2, 4c1, 4c2 and 4c3:
-
Seven tested 2-arylethenylquinoline derivatives
References
Wimo A, Winblad B, Jonsson L (2010) The worldwide societal costs of dementia: estimates for 2009. Alzheimers Dement 6(2):98–103
Rios JA, Cisternas P, Arrese M, Barja S, Inestrosa NC (2014) Is Alzheimer’s disease related to metabolic syndrome? A Wnt signaling conundrum. Prog Neurobiol 121:125–146
Sloane PD, Zimmerman S, Suchindran C, Reed P, Wang L, Boustani M, Sudha S (2002) The public health impact of Alzheimer’s disease 2000–2050: potential implication of treatment advances. Annu Rev Publ Health 23:213–231
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377(9770):1019–1031
Takeda A, Loveman E, Clegg A, Kirby J, Picot J, Payne E, Green C (2006) A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer’s disease. Int J Geriatr Psychiatry 21(1):17–28
Mucke L (2009) Alzheimer’s disease. Nature 461(7266):895–897
Golde TE, Schneider LS, Koo EH (2011) Anti-aβ therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69(2):203–213
Leon R, Garcia AG, Marco-Contelles J (2013) Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 33(1):139–189
Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 3(1):67–72
Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, Younkin S, Duff K, Hardy J, Hutton M (1998) Increased Aβ42 (43) from cell lines expressing presenilin 1 mutations. Ann Neurol 43(2):256–258
Hardy J, Selkoe DJ (2002) Medicine—the amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356
Wang H, Guo X, Jiang S, Tang G (2013) Automated synthesis of [18 F] Florbetaben as Alzheimer’s disease imaging agent based on a synthesis module system. Appl Radiat Isot 71(1):41–46
Kung HF, Lee CW, Zhuang ZP, Kung MP, Hou C, Plossl K (2001) Novel stilbenes as probes for amyloid plaques. J Am Chem Soc 123(50):12740–12741
Lee I, Choe YS, Choi JY, Lee KH, Kim BT (2012) Synthesis and evaluation of 18F-labeled styryltriazole and resveratrol derivatives for β-amyloid plaque imaging. J Med Chem 55(2):883–892
Jiang HL, Wang X, Huang L, Luo ZH, Su T, Ding K, Li XS (2011) Benzenediol-berberine hybrids: multifunctional agents for Alzheimer’s disease. Bioorg Med Chem 19(23):7228–7235
Oz M, Lorke DE, Petroianu GA (2009) Methylene blue and Alzheimer’s disease. Biochem Pharmacol 78(8):927–932
Mancino AM, Hindo SS, Kochi A, Lim MH (2009) Effects of clioquinol on metal-triggered amyloid-β aggregation revisited. Inorg Chem 48(20):9596–9598
Freeman SE, Dawson RM (1991) Tacrine: a pharmacological review. Prog Neurobiol 36(4):257–277
Wang XQ, Xia CL, Chen SB, Tan JH, Ou TM, Huang SL, Li D, Gu LQ, Huang ZS (2015) Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 89:349–361
Bartolini M, Bertucci C, Bolognesi ML, Cavalli A, Melchiorre C, Andrisano V (2007) Insight into the kinetic of amyloid β (1–42) peptide self-aggregation: elucidation of inhibitors’ mechanism of action. ChemBioChem 8(17):2152–2161
Davalos A, Gomez-Cordoves C, Bartolome B (2004) Extending applicability of the oxygen radical absorbance capacity (ORAC-fluorescein) assay. J Agric Food Chem 52(1):48–54
Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77(1):71–94
Sulston JE, White JG (1980) Regulation and cell autonomy during postembryonic development of Caenorhabditis elegans. Dev Biol 78(2):577–597
Avery L, Horvitz HR (1989) Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans. Neuron 3(4):473–485
Link CD (1995) Expression of human β-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 92(20):9368–9372
Dosanjh LE, Brown MK, Rao G, Link CD, Luo Y (2010) Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid-β. J Neurosci 19(2):681–690
Gutierrez-Zepeda A, Santell R, Wu ZX, Brown M, Wu YJ, Khan I, Link CD, Zhao BL, Luo Y (2005) Soy isoflavone glycitein protects against β amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neurosci 6:54
Wu YJ, Wu ZX, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y (2006) Amyloid-β-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26(50):13102–13113
Abbas S, Wink M (2010) Epigallocatechin gallate inhibits beta amyloid oligomerization in Caenorhabditis elegans and affects the daf-2/insulin-like signaling pathway. Phytomedicine 17(11):902–909
Diomede L, Cassata G, Fiordaliso F, Salio M, Ami D, Natalello A, Doglia SM, De Luigi A, Salmona M (2010) Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting oligomers. Neurobiol Dis 40(2):424–431
Dostal V, Roberts CM, Link CD (2010) Genetic mechanisms of coffee extract protection in a Caenorhabditis elegans model of β-amyloid peptide toxicity. Genetics 186(3):857–866
Sangha JS, Sun X, Wally OSD, Zhang K, Ji X, Wang Z, Wang Y, Zidichouski J, Prithiviraj B, Zhang J (2012) Liuwei Dihuang (LWDH), a traditional Chinese medicinal formula, protects against β-amyloid toxicity in transgenic Caenorhabditis elegans. PLoS One 7(8):e43990
Zhang W, Zhi D, Ren H, Wang D, Wang X, Zhang Z, Fei D, Zhu H, Li H (2016) Shengmai formula ameliorates pathological characteristics in AD C. elegans. Cell Mol Neurobiol 36(8):1291–1302
Hobert O, Bulow H (2003) Development and maintenance of neuronal architecture at the ventral midline of C. elegans. Curr Opin Neurobiol 13(1):70–78
Bargmann CI, Hartwieg E, Horvitz HR (1993) Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell 74(3):515–527
Zamberlan DC, Arantes LP, Machado ML, Golombieski R, Soares FAA (2014) Diphenyl-diselenide suppresses amyloid-β peptide in Caenorhabditis elegans model of Alzheimer’s disease. Neuroscience 278:40–50
Lewis JA, Fleming JT (1995) Basic culture methods. Methods Cell Biol 48:3–29
Ura K, Kai T, Sakata S, Iguchi T, Arizono K (2002) Aquatic acute toxicity testing using the nematode Caenorhabditis elegans. J Health Sci 48(6):583–586
Hanukoglu I, Tanese N, Fuchs E (1983) Complementary DNA sequence of a human cytoplasmic actin: interspecies divergence of 3′ non-coding regions. J Mol Biol 163(4):673–678
Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC (2015) The evolution of compositionally and functionally distinct actin filaments. J Cell Sci 128(11):2009–2019
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29 (9)
de Jong WW, Caspers GJ, Leunissen JA (1998) Genealogy of the α-crystallin—small heat-shock protein superfamily. Int J Biol Macromol 22(3–4):151–162
Link CD, Taft A, Kapulkin V, Duke K, Kim S, Fei Q, Wood DE, Sahagan BG (2003) Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer’s disease model. Neurobiol Aging 24(3):397–413
Fonte V, Kapulkin V, Taft A, Fluet A, Friedman D, Link CD (2002) Interaction of intracellular β amyloid peptide with chaperone proteins. Proc Natl Acad Sci USA 99(14):9439–9444
Walsh DM, Selkoe DJ (2004) Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept Lett 11(3):213–228
Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF (2005) Soluble β-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 25(48):11061–11070
Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-β protein assembly in the brain impairs memory. Nature 440(7082):352–357
Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, LaFerla FM (2006) Temporal profile of amyloid-β (Aβ) oligomerization in an in vivo model of Alzheimer disease—a link between Aβ and tau pathology. J Biol Chem 281(3):1599–1604
Acknowledgements
The nematode strains used in this work were provided by the Caenorhabditis Genetics Center (CGC), which is funded by the NIH National Center for Research Resources. The authors gratefully acknowledge the financial supports from National Natural Science Foundation of China (Grant Nos. 21375152, 21675177 and 81273433) and Guangdong Provincial Science and Technology Projects (Grant No. 2016B030303002).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
He, Q., Huang, G., Chen, Y. et al. The protection of novel 2-arylethenylquinoline derivatives against impairment of associative learning memory induced by neural Aβ in C. elegans Alzheimer’s disease model. Neurochem Res 42, 3061–3072 (2017). https://doi.org/10.1007/s11064-017-2339-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-017-2339-0