阿茲海默氏症(Alzheimer's disease, AD)是最常見的神經退化性疾病之一，好發於65歲以上的老年人口，阿茲海默氏症主要是由β-類澱粉蛋白(amyloid beta, Aβ)堆積形成類澱粉斑塊(amyloid plaques)和過度磷酸化Tau蛋白(p-tau)造成的神經纖維糾結導致神經細胞的損傷。先前研究顯示，Aβ會聚集形成不同的型態(forms)，其中寡聚類澱粉蛋白(Aβ oligomer)具有較高的毒性。所以發展具有抑制Aβ聚集(aggregation)的藥物是治療阿茲海默氏症的策略之一。在我們先前的實驗中發現，兩年大的阿茲海默氏症模式鼠中，具有較高表現的Protein-X。為了確認Protein-X在阿茲海默氏症中的機制，我們建立了Protein-X stable transfected SH-SY5Y的細胞株。發現Protein-X表現的情況下，細胞產生較高的細胞毒性之寡聚合Aβ聚集(Aβ oligomerization)。我們也在黨參中發現化合物9(C-9)，可以降低細胞毒性及寡聚合Aβ的聚集。故是發展治療阿茲海默氏症藥物的潛力藥物。

Alzheimer’s disease (AD), the most common neurodegenerative disease, usually occurs in people over 65 years of age. AD is well known caused by the accumulation of misfolded amyloid beta (Aβ) plaques and hyperphosphorylated tau protein-containing neurofibrillary tangles, leading to neuronal cell death. Many studies showed that Aβ oligomer has higher toxicity than that of Aβ monomers, and the development of potential drug which can reduce or inhibit the formation of Aβ oligomer would possibly prevent AD. Previously, we found that Protein-X is highly expressed in 2 years old triple transgenic AD mice [PS1(M146V), APP(K670M/N671L), tau(P301L)]. To confirm the effects of Protein-X in AD pathway, we recently generated Protein-X stable transfected SH-SY5Y cell line, and found that SH-SY5Y cells are more sensitive to Aβ treatment and have higher Aβ oligomerization in the presence of Protein-X. We also identified that compound-9 (C-9) which is isolated for Codonopsis pilosula (CP) can reduce Aβ formation and cytotoxicity in Protein-X stable transfected Sh-SY5Y cells. Based on the these results, C-9 could be a potential therapeutic drug for the treatment of AD.

References

1 Hardy, J. & Selkoe, D. J. The amyloid hypothesis of alzheimer's disease: Progress and problems on the road to therapeutics. Science 297, 353-356, doi:10.1126/science.1072994 (2002).
2 Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C. E., Jondro, P. D., Schmidt, S. D., Wang, K. & et al. Candidate gene for the chromosome 1 familial alzheimer's disease locus. Science 269, 973-977 (1995).
3 Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J. F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I. et al. Cloning of a gene bearing missense mutations in early-onset familial alzheimer's disease. Nature 375, 754-760, doi:10.1038/375754a0 (1995).
4 Wisniewski, T., Ghiso, J. & Frangione, B. Peptides homologous to the amyloid protein of alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochemical and biophysical research communications 179, 1247-1254 (1991).
5 MacLeod, R., Hillert, E. K., Cameron, R. T. & Baillie, G. S. The role and therapeutic targeting of alpha-, beta- and gamma-secretase in alzheimer's disease. Future science OA 1, FSO11, doi:10.4155/fso.15.9 (2015).
6 Sengupta, U., Nilson, A. N. & Kayed, R. The role of amyloid-beta oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 6, 42-49, doi:10.1016/j.ebiom.2016.03.035 (2016).
7 Kang, S., Lee, Y. H. & Lee, J. E. Metabolism-centric overview of the pathogenesis of alzheimer's disease. Yonsei medical journal 58, 479-488, doi:10.3349/ymj.2017.58.3.479 (2017).
8 Blennow, K., de Leon, M. J. & Zetterberg, H. Alzheimer's disease. Lancet 368, 387-403, doi:10.1016/S0140-6736(06)69113-7 (2006).
9 Suh, Y. H. & Checler, F. Amyloid precursor protein, presenilins, and alpha-synuclein: Molecular pathogenesis and pharmacological applications in alzheimer's disease. Pharmacological reviews 54, 469-525 (2002).
10 Terum, T. M., Andersen, J. R., Rongve, A., Aarsland, D., Svendsboe, E. J. & Testad, I. The relationship of specific items on the neuropsychiatric inventory to caregiver burden in dementia: A systematic review. International journal of geriatric psychiatry, doi:10.1002/gps.4704 (2017).
11 Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K. & Muller-Hill, B. The precursor of alzheimer's disease amyloid a4 protein resembles a cell-surface receptor. Nature 325, 733-736, doi:10.1038/325733a0 (1987).
12 Gupta, A. & Goyal, R. Amyloid beta plaque: A culprit for neurodegeneration. Acta neurologica Belgica 116, 445-450, doi:10.1007/s13760-016-0639-9 (2016).
13 Cole, S. L. & Vassar, R. The role of amyloid precursor protein processing by bace1, the beta-secretase, in alzheimer disease pathophysiology. The Journal of biological chemistry 283, 29621-29625, doi:10.1074/jbc.R800015200 (2008).
14 Cole, S. L. & Vassar, R. The basic biology of bace1: A key therapeutic target for alzheimer's disease. Current genomics 8, 509-530, doi:10.2174/138920207783769512 (2007).
15 Selkoe, D. J. Alzheimer's disease: Genes, proteins, and therapy. Physiological reviews 81, 741-766 (2001).
16 Barage, S. H. & Sonawane, K. D. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in alzheimer's disease. Neuropeptides 52, 1-18, doi:10.1016/j.npep.2015.06.008 (2015).
17 Ahmed, M., Davis, J., Aucoin, D., Sato, T., Ahuja, S., Aimoto, S., Elliott, J. I., Van Nostrand, W. E. & Smith, S. O. Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nature structural & molecular biology 17, 561-567, doi:10.1038/nsmb.1799 (2010).
18 Masuzzo, A., Dinet, V., Cavanagh, C., Mascarelli, F. & Krantic, S. Amyloidosis in retinal neurodegenerative diseases. Frontiers in neurology 7, 127, doi:10.3389/fneur.2016.00127 (2016).
19 Navarro, S., Diaz-Caballero, M., Illa, R. & Ventura, S. Aggregation propensity of neuronal receptors: Potential implications in neurodegenerative disorders. Future science OA 1, FSO39, doi:10.4155/fso.15.39 (2015).
20 Walsh, D. M. & Selkoe, D. J. A beta oligomers - a decade of discovery. Journal of neurochemistry 101, 1172-1184, doi:10.1111/j.1471-4159.2006.04426.x (2007).
21 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., Regan, C. M., Walsh, D. M., Sabatini, B. L. & Selkoe, D. J. Amyloid-beta protein dimers isolated directly from alzheimer's brains impair synaptic plasticity and memory. Nature medicine 14, 837-842, doi:10.1038/nm1782 (2008).
22 Qian, Y., Yin, J., Hong, J., Li, G., Zhang, B., Liu, G., Wan, Q. & Chen, L. Neuronal seipin knockout facilitates abeta-induced neuroinflammation and neurotoxicity via reduction of ppargamma in hippocampus of mouse. Journal of neuroinflammation 13, 145, doi:10.1186/s12974-016-0598-3 (2016).
23 St George-Hyslop, P. & Haass, C. Regulatory rna goes awry in alzheimer's disease. Nature medicine 14, 711-712, doi:10.1038/nm0708-711 (2008).
24 Faghihi, M. A., Modarresi, F., Khalil, A. M., Wood, D. E., Sahagan, B. G., Morgan, T. E., Finch, C. E., St Laurent, G., 3rd, Kenny, P. J. & Wahlestedt, C. Expression of a noncoding rna is elevated in alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nature medicine 14, 723-730, doi:10.1038/nm1784 (2008).
25 Kim, J. H. Brain-derived neurotrophic factor exerts neuroprotective actions against amyloid beta-induced apoptosis in neuroblastoma cells. Experimental and therapeutic medicine 8, 1891-1895, doi:10.3892/etm.2014.2033 (2014).
26 Meraz-Rios, M. A., Toral-Rios, D., Franco-Bocanegra, D., Villeda-Hernandez, J. & Campos-Pena, V. Inflammatory process in alzheimer's disease. Frontiers in integrative neuroscience 7, 59, doi:10.3389/fnint.2013.00059 (2013).
27 Wang, K., Yao, Y., Zhu, X., Zhang, K., Zhou, F. & Zhu, L. Amyloid beta induces nlrp3 inflammasome activation in retinal pigment epithelial cells via nadph oxidase- and mitochondria-dependent ros production. Journal of biochemical and molecular toxicology, doi:10.1002/jbt.21887 (2016).
28 Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L., Finch, C. E., Frautschy, S., Griffin, W. S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I. R., McGeer, P. L. et al. Inflammation and alzheimer's disease. Neurobiology of aging 21, 383-421 (2000).
29 Liu, Q., Chen, Y., Shen, C., Xiao, Y., Wang, Y., Liu, Z. & Liu, X. Chicoric acid supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of nf-kappab. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, doi:10.1096/fj.201601071R (2016).
30 Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y. & LaFerla, F. M. Triple-transgenic model of alzheimer's disease with plaques and tangles: Intracellular abeta and synaptic dysfunction. Neuron 39, 409-421 (2003).
31 Li, X., Cui, J., Yu, Y., Li, W., Hou, Y., Wang, X., Qin, D., Zhao, C., Yao, X., Zhao, J. & Pei, G. Traditional chinese nootropic medicine radix polygalae and its active constituent onjisaponin b reduce beta-amyloid production and improve cognitive impairments. PloS one 11, e0151147, doi:10.1371/journal.pone.0151147 (2016).
32 Tseng, Y. T., Chang, F. R. & Lo, Y. C. The chinese herbal formula liuwei dihuang protects dopaminergic neurons against parkinson's toxin through enhancing antioxidative defense and preventing apoptotic death. Phytomedicine : international journal of phytotherapy and phytopharmacology 21, 724-733, doi:10.1016/j.phymed.2013.11.001 (2014).
33 Heng, Y., Zhang, Q. S., Mu, Z., Hu, J. F., Yuan, Y. H. & Chen, N. H. Ginsenoside rg1 attenuates motor impairment and neuroinflammation in the mptp-probenecid-induced parkinsonism mouse model by targeting alpha-synuclein abnormalities in the substantia nigra. Toxicology letters 243, 7-21, doi:10.1016/j.toxlet.2015.12.005 (2016).
34 Jin, S., Kedia, N., Illes-Toth, E., Haralampiev, I., Prisner, S., Herrmann, A., Wanker, E. E. & Bieschke, J. Amyloid-beta(1-42) aggregation initiates its cellular uptake and cytotoxicity. The Journal of biological chemistry 291, 19590-19606, doi:10.1074/jbc.M115.691840 (2016).
35 Kumar, G. P. & Khanum, F. Neuroprotective potential of phytochemicals. Pharmacognosy reviews 6, 81-90, doi:10.4103/0973-7847.99898 (2012).
36 Kayed, R. & Lasagna-Reeves, C. A. Molecular mechanisms of amyloid oligomers toxicity. Journal of Alzheimer's disease : JAD 33 Suppl 1, S67-78, doi:10.3233/JAD-2012-129001 (2013).
37 Puzzo, D., Lee, L., Palmeri, A., Calabrese, G. & Arancio, O. Behavioral assays with mouse models of alzheimer's disease: Practical considerations and guidelines. Biochemical pharmacology 88, 450-467, doi:10.1016/j.bcp.2014.01.011 (2014).