阿茲海默症 (Alzheimer's disease) 是全世界失智症最常見的形式，佔了失智症病例的60-80%。發病的主要假設為β-澱粉樣蛋白 (β-amyloid, Aβ) 的累積和tau蛋白過度磷酸化，兩者均可導致神經元死亡和失智症狀的出現。甲基乙二醛 (Methylglyoxal, MG) 為一種高反應性的雙羰基醛類化合物，同時也為糖化終產物 (Advanced glycation end-products, AGEs) 的前驅物。許多研究也證實MG會造成神經損傷導致神經退化性疾病的發生，且AGEs也會加劇Aβ及磷酸化tau蛋白的產生。有研究指出沒食子酸丙酯 (Propyl gallate, PG) 可以與MG結合，並抑制超過77.5%的MG。故本實驗將MG添加於飲用水中讓小鼠飲用，並以管餵的方式探討20、40及100 mg/kg不同劑量之PG對MG誘導腦神經損傷之保護效果。在莫里斯水迷宮試驗中，給予PG能夠縮短小鼠找到平台的時間，改善小鼠的空間認知障礙，於新物體識別試驗也能發現MG組小鼠的辨別率只有0.34 ± 0.02，而在給予不同劑量的PG後，其辨別率提升為0.59 ± 0.01、0.65 ± 0.01與0.73 ± 0.03，可以依據劑量效應減少小鼠的長期記憶能力受損，並且於曠場試驗中餵食PG的小鼠可以表現出較佳的抗焦慮能力。西方墨點法的結果也顯示，給予PG後可以增加小鼠腦中PI3K、p-Akt、p-GSK-3β的蛋白表現量，進而抑制MG所造成的tau蛋白過度磷酸化和Aβ的生成，並改善海馬迴中的發炎反應，降低TNF-α及IL-6的蛋白質表現。此外，組織病理切片中可以看到給予PG能減少MG誘導產生的神經元功能障礙及神經元死亡，經過免疫組織化學染色也發現藉由PG的給予可以減少MG誘導的海馬迴tau蛋白過度磷酸化。且於血液生化數值分析中，ALT值的結果顯示給予20、40及100 mg/kg 的PG並不會對小鼠造成明顯的肝毒性。總結以上結果，PG具有保護MG誘導小鼠產生的腦神經損傷作用以及改善小鼠的認知能力下降之潛力。

Alzheimer's disease (AD) is the most common form of dementia worldwide and involves 60-80% of all reported dementias. The main hypothesis of pathogenesis focuses on the β-amyloid accumulation and tau hyperphosphorylation, both of which can lead to neuronal death and subsequent dementia. Methylglyoxal (MG) is a highly reactive dicarbonyl aldehyde, it is also the precursor of the advanced glycation end-products (AGEs). MG has been proved to be toxic to neuron and may be the reason of many neurodegenerative diseases, and AGEs also increased the production of Aβ and phosphorylated tau protein. Some studies indicated that Propyl gallate (PG) can bind to MG to form adduct and suppressed more than 77.5% MG. In this experiment, MG was added to drinking water of mice, and 20, 40 and 100 mg/kg of PG were administered orally to evaluate the protective effects of PG on MG-induced brain nerve injury in mice. In Morris water maze test, giving PG can shorten the time for mice to find the platform, which indicated the spatial cognitive impairment of mice was improved. In novel object recognition test, it can also showed that the discrimination ratio of mice in MG group was only 0.34 ± 0.02, and after treated with different doses of PG, the discrimination ratio increased to 0.59 ± 0.01, 0.65 ± 0.01 and 0.73 ± 0.03, which can be based on the dose effect to reduce impairment of long-term memory in mice. Moreover, the mice fed with PG showed better anxiolytic ability in the open field test than those of MG group. In western blot, the results showed that PG increased the protein expression of PI3K, p-Akt, p-GSK-3β of hippocampus in mice, and inhibiting MG-caused hyperphosphorylation of tau protein and Aβ accumulation. PG also reduced the protein expression of TNF-α and IL-6, representing that it improved the inflammatory response in the hippocampus. In addition, the results of histopathological examination indicated that administration of PG reduced neuronal dysfunction and neuronal death induced by MG. Immunohistochemical staining also showed that trapping of MG by PG reduced the hyperphosphorylation of tau protein of hippocampus in mice. In the analysis of blood biochemical parameters, the result of ALT levels indicated that 20, 40, and 100 mg/kg of PG treatment did not cause significant hepatotoxicity in mice. In summary, PG has the potential to protect the brain nerve damage induced by MG in mice and to improve the cognitive decline of mice.

Abordo, E. A., Minhas, H. S., & Thornalley, P. J. (1999). Accumulation of α-oxoaldehydes during oxidative stress: a role in cytotoxicity. Biochemical Pharmacology, 58(4), 641-648.
Alzheimer's Association. (2021). 2021 Alzheimer's disease facts and figures. Alzheimers Dement, 17(3), 327-406.
Ashrafian, H., Zadeh, E. H., & Khan, R. H. (2021). Review on Alzheimer's disease: Inhibition of amyloid beta and tau tangle formation. International Journal of Biological Macromolecules, 167, 382-394.
Awasthi, M., Singh, S., Pandey, V. P., & Dwivedi, U. N. (2016). Alzheimer's disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products. Journal of the Neurological Sciences, 361, 256-271.
Baldi, E., Efoudebe, M., Lorenzini, C. A., & Bucherelli, C. (2005). Spatial navigation in the Morris water maze: working and long lasting reference memories. Neuroscience Letters, 378(3), 176-180.
Bharani, K. L., Ledreux, A., Gilmore, A., Carroll, S. L., & Granholm, A. C. (2020). Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer's disease. Neurobiology of Aging, 87, 49-59.
Bruni, A. C., Bernardi, L., & Gabelli, C. (2020). From beta amyloid to altered proteostasis in Alzheimer's disease. Ageing Research Reviews, 64, 101126.
Buchhave, P., Zetterberg, H., Blennow, K., Minthon, L., Janciauskiene, S., & Hansson, O. (2010). Soluble TNF receptors are associated with Aβ metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiology of Aging, 31(11), 1877-1884.
Cano, A., Ettcheto, M., Chang, J. H., Barroso, E., Espina, M., Kühne, B. A., Barenys, M., Auladell, C., Folch, J., Souto, E. B., Camins, A., Turowski, P., & García, M. L. (2019). Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer's disease mice model. Journal of controlled release, 301, 62-75.
Cap, K. C., Jung, Y. J., Choi, B. Y., Hyeon, S. J., Kim, J. G., Min, J. K., Islam, R., Hossain, A. J., Chung, W. S., Suh, S. W., Ryu, H., & Park, J. B. (2020). Distinct dual roles of p-Tyr42 RhoA GTPase in tau phosphorylation and ATP citrate lyase activation upon different Aβ concentrations. Redox Biology, 32, 101446.
Chu, J. M. T., Lee, D. K. M., Wong, D. P. K., Wong, R. N. S., Yung, K. K. L., Cheng, C. H. K., & Yue, K. K. M. (2014). Ginsenosides attenuate methylglyoxal-induced impairment of insulin signaling and subsequent apoptosis in primary astrocytes. Neuropharmacology, 85, 215-223.
Cohen, S. J., & Stackman, R. W., Jr. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behavioural brain research, 285, 105-117.
Colzani, M., De Maddis, D., Casali, G., Carini, M., Vistoli, G., & Aldini, G. (2016). Reactivity, selectivity, and reaction mechanisms of aminoguanidine, hydralazine, pyridoxamine, and carnosine as sequestering agents of reactive carbonyl species: A comparative study. ChemMedChem, 11(16), 1778-1789.
Cui, H., Tao, F., Hou, Y., Lu, Y., Zheng, T., Sang, S., & Lv, L. (2018). Dual effects of propyl gallate and its methylglyoxal adduct on carbonyl stress and oxidative stress. Food Chemistry, 265, 227-232.
Di Loreto, S., Zimmitti, V., Sebastiani, P., Cervelli, C., Falone, S., & Amicarelli, F. (2008). Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons. The International Journal of Biochemistry & Cell Biology, 40(2), 245-257.
Dumurgier, J., & Sabia, S. (2020). Epidemiology of Alzheimer's disease: latest trends. La Revue du Praticien, 70(2), 149-151.
Ewen, S. T., Fauzi, A., Quan, T. Y., Chamyuang, S., & Yin, A. C. Y. (2021). A review on advances of treatment modalities for Alzheimer's disease. Life Sciences, 119129.
Fuller, S., Münch, G., & Steele, M. (2009). Activated astrocytes: a therapeutic target in Alzheimer's disease? Expert Rev Neurother, 9(11), 1585-1594.
Götz, J., Ittner, L. M., & Schonrock, N. (2006). Alzheimer's disease and frontotemporal dementia: prospects of a tailored therapy? Medical Journal of Australia, 185(7), 381-384.
Gasser, T. (2009). Mendelian forms of Parkinson's disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1792(7), 587-596.
Geng, J., Wang, L., Zhang, L., Qin, C., Song, Y., Ma, Y., Chen, Y., Chen, S., Wang, Y., Zhang, Z., & Yang, G. Y. (2018). Blood-brain barrier disruption induced cognitive impairment is associated with increase of inflammatory cytokine. Frontiers in aging neuroscience, 10, 129-129.
Gálico, D. A., Nova, C. V., Guerra, R. B., & Bannach, G. (2015). Thermal and spectroscopic studies of the antioxidant food additive propyl gallate. Food Chemistry, 182, 89-94.
Ham, J., Lim, W., Park, S., Bae, H., You, S., & Song, G. (2019). Synthetic phenolic antioxidant propyl gallate induces male infertility through disruption of calcium homeostasis and mitochondrial function. Environmental Pollution, 248, 845-856.
Hammes, H. P. (2003). Pathophysiological mechanisms of diabetic angiopathy. Journal of Diabetes and its Complications, 17, 16-19.
Hansen, F., Pandolfo, P., Galland, F., Torres, F. V., Dutra, M. F., Batassini, C., Guerra, M. C., Leite, M. C., & Gonçalves, C. A. (2016). Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain. Physiology & Behavior, 164, 93-101.
Herculano-Houzel, S. (2009). The human brain in numbers: a linearly scaled-up primate brain. Frontiers in Human Neuroscience, 3, 31.
Hill, A. S., Sahay, A., & Hen, R. (2015). Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology, 40(10), 2368-2378.
Hou, Y., Xie, Z., Cui, H., Lu, Y., Zheng, T., Sang, S., & Lv, L. (2018). Trapping of glyoxal by propyl, octyl and dodecyl gallates and their mono-glyoxal adducts. Food Chemistry, 269, 396-403.
Huang, W., Cheng, P., Yu, K., Han, Y., Song, M., & Li, Y. (2017). Hyperforin attenuates aluminum-induced Aβ production and Tau phosphorylation via regulating Akt/GSK-3β signaling pathway in PC12 cells. Biomedicine & Pharmacotherapy, 96, 1-6.
John, A., & Reddy, P. H. (2021). Synaptic basis of Alzheimer's disease: Focus on synaptic amyloid beta, p-tau and mitochondria. Ageing Research Reviews, 65, 101208.
Kamathe, R. S., & Joshi, K. R. (2018). A novel method based on independent component analysis for brain MR image tissue classification into CSF, WM and GM for atrophy detection in Alzheimer's disease. Biomedical Signal Processing and Control, 40, 41-48.
Kandimalla, R., Thirumala, V., & Reddy, P. H. (2017). Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(5), 1078-1089.
Kold-Christensen, R., & Johannsen, M. (2020). Methylglyoxal metabolism and aging-related disease: Moving from correlation toward causation. Trends in Endocrinology & Metabolism, 31(2), 81-92.
Krautwald, M., & Münch, G. (2010). Advanced glycation end products as biomarkers and gerontotoxins – A basis to explore methylglyoxal-lowering agents for Alzheimer's disease? Experimental Gerontology, 45(10), 744-751.
Kubis-Kubiak, A. M., Rorbach-Dolata, A., & Piwowar, A. (2019). Crucial players in Alzheimer's disease and diabetes mellitus: Friends or foes? Mechanisms of Ageing and Development, 181, 7-21.
Lauretti, E., Dincer, O., & Praticò, D. (2020). Glycogen synthase kinase-3 signaling in Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1867(5), 118664.
Lee, E. B., Skovronsky, D. M., Abtahian, F., Doms, R. W., & Lee, V. M. Y. (2003). Secretion and intracellular generation of truncated Aβ in β-Site amyloid-β precursor protein-cleaving enzyme expressing human neurons. Journal of Biological Chemistry, 278(7), 4458-4466.
Li, X. H., Lv, B. L., Xie, J. Z., Liu, J., Zhou, X. W., & Wang, J. Z. (2012). AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiology of Aging, 33(7), 1400-1410.
Li, X., Zheng, T., Sang, S., & Lv, L. (2014). Quercetin inhibits advanced glycation end product formation by trapping methylglyoxal and glyoxal. Journal of Agricultural and Food Chemistry, 62(50), 12152-12158.
Li, X. H., Du, L. L., Cheng, X. S., Jiang, X., Zhang, Y., Lv, B. L., Liu, R., Wang, J. Z., & Zhou, X. W. (2013). Glycation exacerbates the neuronal toxicity of β-amyloid. Cell Death & Disease, 4(6), e673-e673.
Li, X. H., Xie, J. Z., Jiang, X., Lv, B. L., Cheng, X. S., Du, L. L., Zhang, J. Y., Wang, J. Z., & Zhou, X. W. (2012). Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation. NeuroMolecular Medicine, 14(4), 338-348.
Liu, S. J., Zhang, A. H., Li, H. L., Wang, Q., Deng, H. M., Netzer, W. J., Xu, H., & Wang, J. Z. (2003). Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. Journal of Neurochemistry, 87(6), 1333-1344.
Liu, S. J., Zhang, J. Y., Li, H. L., Fang, Z. Y., Wang, Q., Deng, H. M., Gong, C. X., Grundke-Iqbal, I., Iqbal, K., & Wang, J. Z. (2004). Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. Journal of Biological Chemistry, 279(48), 50078-50088.
Lubitz, I., Ricny, J., Atrakchi-Baranes, D., Shemesh, C., Kravitz, E., Liraz-Zaltsman, S., Maksin-Matveev, A., Cooper, I., Leibowitz, A., Uribarri, J., Schmeidler, J., Cai, W., Kristofikova, Z., Ripova, D., LeRoith, D., & Schnaider-Beeri, M. (2016). High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model. Aging cell, 15(2), 309-316.
Lucas, J. J., Hernández, F., Gómez-Ramos, P., Morán, M. A., Hen, R., & Avila, J. (2001). Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. The EMBO journal, 20(1-2), 27-39.
Lv, L., Shao, X., Chen, H., Ho, C. T., & Sang, S. (2011). Genistein inhibits advanced glycation end product formation by trapping methylglyoxal. Chemical Research in Toxicology, 24(4), 579-586.
Münch, G., Thome, J., Foley, P., Schinzel, R., & Riederer, P. (1997). Advanced glycation endproducts in ageing and Alzheimer's disease. Brain Research Reviews, 23(1), 134-143.
Münch, G., Mayer, S., Michaelis, J., Hipkiss, A. R., Riederer, P., Müller, R., Neumann, A., Schinzel, R., & Cunningham, A. M. (1997). Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of β-amyloid peptide. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1360(1), 17-29.
Maessen, D. E., Stehouwer, C. D., & Schalkwijk, C. G. (2015). The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases. Clinical Science (Lond), 128(12), 839-861.
Malafaia, D., Albuquerque, H. M. T., & Silva, A. M. S. (2021). Amyloid-β and tau aggregation dual-inhibitors: A synthetic and structure-activity relationship focused review. European Journal of Medicinal Chemistry, 214, 113209.
Malik, N. S., & Meek, K. M. (1994). The Inhibition of Sugar-Induced Structural Alterations in Collagen by Aspirin and Other Compounds. Biochemical and Biophysical Research Communications, 199(2), 683-686.
Matafome, P., Sena, C., & Seiça, R. (2013). Methylglyoxal, obesity, and diabetes. Endocrine, 43(3), 472-484.
Mega, M. S., Cummings, J. L., Fiorello, T., & Gornbein, J. (1996). The spectrum of behavioral changes in Alzheimer's disease. Neurology, 46(1), 130-135.
Meng, Q., Li, S., Huang, J., Wei, C. C., Wan, X., Sang, S., & Ho, C. T. (2019). Importance of the Nucleophilic Property of Tea Polyphenols. Journal of Agricultural and Food Chemistry, 67(19), 5379-5383.
Miyata, T., van Ypersele de Strihou, C., Ueda, Y., Ichimori, K., Inagi, R., Onogi, H., Ishikawa, N., Nangaku, M., & Kurokawa, K. (2002). Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms. Journal of the American Society of Nephrology, 13(10), 2478-2487.
Morris, R. G., Garrud, P., Rawlins, J. N., & O'Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297(5868), 681-683.
Nan, F., Sun, G., Xie, W., Ye, T., Sun, X., Zhou, P., Dong, X., Sun, J., Sun, X., & Zhang, M. (2019). Ginsenoside Rb1 mitigates oxidative stress and apoptosis induced by methylglyoxal in SH-SY5Y cells via the PI3K/Akt pathway. Molecular and Cellular Probes, 48, 101469.
National Toxicology Program. (1982). NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). National Toxicology Program Technical Reports Index Ser, 240, 1-152.
Navarro, M., & Morales, F. J. (2015). Mechanism of reactive carbonyl species trapping by hydroxytyrosol under simulated physiological conditions. Food Chemistry, 175, 92-99.
Ou, J., Huang, J., Wang, M., & Ou, S. (2017). Effect of rosmarinic acid and carnosic acid on AGEs formation in vitro. Food Chemistry, 221, 1057-1061.
Pedersen, J. T., & Sigurdsson, E. M. (2015). Tau immunotherapy for Alzheimer's disease. Trends in Molecular Medicine, 21(6), 394-402.
Pentkowski, N. S., Rogge-Obando, K. K., Donaldson, T. N., Bouquin, S. J., & Clark, B. J. (2021). Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology. Neuroscience & Biobehavioral Reviews, 127, 647-658.
Rahbar, S., & Figarola, J. L. (2003). Novel inhibitors of advanced glycation endproducts. Archives of Biochemistry and Biophysics, 419(1), 63-79.
Robinson, S. R., Bishop, G. M., & Münch, G. (2003). Alzheimer vaccine: amyloid-beta on trial. Bioessays, 25(3), 283-288.
Sang, S., Shao, X., Bai, N., Lo, C. Y., Yang, C. S., & Ho, C. T. (2007). Tea Polyphenol (−)-Epigallocatechin-3-Gallate: A new trapping agent of reactive dicarbonyl species. Chemical Research in Toxicology, 20(12), 1862-1870.
Sasaki, N., Fukatsu, R., Tsuzuki, K., Hayashi, Y., Yoshida, T., Fujii, N., Koike, T., Wakayama, I., Yanagihara, R., Garruto, R., Amano, N., & Makita, Z. (1998). Advanced Glycation End Products in Alzheimer's Disease and Other Neurodegenerative Diseases. The American Journal of Pathology, 153(4), 1149-1155.
Scheijen, J. L., & Schalkwijk, C. G. (2014). Quantification of glyoxal, methylglyoxal and 3-deoxyglucosone in blood and plasma by ultra performance liquid chromatography tandem mass spectrometry: evaluation of blood specimen. Clinical Chemistry and Laboratory Medicine, 52(1), 85-91.
Seibenhener, M. L., & Wooten, M. C. (2015). Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. Journal of visualized experiments: JoVE(96), e52434-e52434.
Sena, C. M., Matafome, P., Crisóstomo, J., Rodrigues, L., Fernandes, R., Pereira, P., & Seiça, R. M. (2012). Methylglyoxal promotes oxidative stress and endothelial dysfunction. Pharmacological Research, 65(5), 497-506.
Shamsi, A., Shahwan, M., Husain, F. M., & Khan, M. S. (2019). Characterization of methylglyoxal induced advanced glycation end products and aggregates of human transferrin: Biophysical and microscopic insight. International Journal of Biological Macromolecules, 138, 718-724.
Shao, X., Bai, N., He, K., Ho, C. T., Yang, C. S., & Sang, S. (2008). Apple polyphenols, phloretin and phloridzin: new trapping agents of reactive dicarbonyl species. Chemical Research in Toxicology, 21(10), 2042-2050.
Steen, E., Terry, B. M., Rivera, E. J., Cannon, J. L., Neely, T. R., Tavares, R., Xu, X. J., Wands, J. R., & de la Monte, S. M. (2005). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? Journal of Alzheimer's Disease, 7(1), 63-80.
Taguchi, T., Sugiura, M., Hamada, Y., & Miwa, I. (1998). In vivo formation of a schiff base of aminoguanidine with pyridoxal phosphate. Biochemical Pharmacology, 55(10), 1667-1671.
Thornalley, P. J., Jahan, I., & Ng, R. (2001). Suppression of the accumulation of triosephosphates and increased formation of methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro. The Journal of Biochemistry, 129(4), 543-549.
Totlani, V. M., & Peterson, D. G. (2006). Epicatechin Carbonyl-Trapping Reactions in Aqueous Maillard Systems:  Identification and Structural Elucidation. Journal of Agricultural and Food Chemistry, 54(19), 7311-7318.
Tucker, L. B., Velosky, A. G., & McCabe, J. T. (2018). Applications of the Morris water maze in translational traumatic brain injury research. Neuroscience & Biobehavioral Reviews, 88, 187-200.
Vorhees, C. V., & Williams, M. T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature protocols, 1(2), 848-858.
Wang, J. Z., & Liu, F. (2008). Microtubule-associated protein tau in development, degeneration and protection of neurons. Progress in Neurobiology, 85(2), 148-175.
Wang, W., Yang, R., Yao, H., Wu, Y., Pan, W., & Jia, A. Q. (2019). Inhibiting the formation of advanced glycation end-products by three stilbenes and the identification of their adducts. Food Chemistry, 295, 10-15.
Webster, J., Urban, C., Berbaum, K., Loske, C., Alpar, A., Gärtner, U., de Arriba, S. G., Arendt, T., & Münch, G. (2005). The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal. Neurotoxicity Research, 7(1-2), 95-101.
Więckowska-Gacek, A., Mietelska-Porowska, A., Wydrych, M., & Wojda, U. (2021). Western diet as a trigger of Alzheimer's disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration. Ageing Research Reviews, 101397.
Wolffenbuttel, B. H., Boulanger, C. M., Crijns, F. R., Huijberts, M. S., Poitevin, P., Swennen, G. N., Vasan, S., Egan, J. J., Ulrich, P., Cerami, A., & Lévy, B. I. (1998). Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proceedings of the National Academy of Sciences of the United States of America, 95(8), 4630-4634.
Xiong, R., Wang, X. L., Wu, J. M., Tang, Y., Qiu, W. Q., Shen, X., Teng, J. F., Pan, R., Zhao, Y., Yu, L., Liu, J., Chen, H. X., Qin, D. L., Yu, C. L., & Wu, A. G. (2020). Polyphenols isolated from lychee seed inhibit Alzheimer's disease-associated Tau through improving insulin resistance via the IRS-1/PI3K/Akt/GSK-3β pathway. Journal of Ethnopharmacology, 251, 112548.
Yamamoto, M., Kiyota, T., Horiba, M., Buescher, J. L., Walsh, S. M., Gendelman, H. E., & Ikezu, T. (2007). Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice. The American Journal of Pathology, 170(2), 680-692.
Yao, Y., Wang, Y., Kong, L., Chen, Y., & Yang, J. (2019). Osthole decreases tau protein phosphorylation via PI3K/AKT/GSK-3β signaling pathway in Alzheimer's disease. Life Sciences, 217, 16-24.
Zhang, Z. X., Zhao, R. P., Wang, D. S., & Wang, A. N. (2016). Fuzhisan ameliorates Aβ production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study. Experimental Gerontology, 84, 88-95.
Zheng, J., Guo, H., Ou, J., Liu, P., Huang, C., Wang, M., Simal-Gandara, J., Battino, M., Jafari, S. M., Zou, L., Ou, S., & Xiao, J. (2021). Benefits, deleterious effects and mitigation of methylglyoxal in foods: A critical review. Trends in Food Science & Technology, 107, 201-212.
Zheng, R., Zhang, Z. H., Chen, C., Chen, Y., Jia, S. Z., Liu, Q., Ni, J. Z., & Song, G. L. (2017). Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease. Biochemical and Biophysical Research Communications, 485(1), 6-15.