Alzheimer’s disease (AD) is the most prevalent cause of dementia worldwide more frequently manifested in postmenopausal women. It has been associated in part with genetic predisposition (Apo E polymorphism) and chronic inflammation. We tested the effects of combinations of genistein with daidzein (SERMs), inositol hexa-phosphate with choline (phospholipid precursors), and the mixture (the Mix) of these two compositions with select plant extracts, vitamins, and minerals on specific AD cellular markers. The tests were conducted on fibroblasts derived from an old female AD patient and human normal dermal fibroblasts (HNDF) cultured under normal and inflammatory conditions. Evaluations included gene and protein expression for APOE, Tau and proinflammatory genes CSF2 and PTGS2. The Mix significantly decreased APOE gene expression in the cells derived from AD donor under normal and IL1β-induced inflammatory conditions. In the presence of IL1β and TNFα, Tau gene expression was significantly lower in both HNDF and AD fibroblasts compared to control. In the presence of TNFα Tau protein was affected by SERMs, phospholipids precursors, and the Mix. Test combinations differently affected the basal and inflammation-induced CSF2 and PTGS2 genes expression in HNDF and AD fibroblast. The effects of these natural compositions were compared to 17β estradiol and inflammatory signaling pathways’ inhibitors (SAPKs) to identify nutrients affecting specific cellular targets. This study indicates that nutrient combinations containing SERMs and/or phospholipid precursors, might exert the protective role of estrogens in relation to AD. These results merit further investigations aimed at developing effective natural approaches to AD and other forms of dementia.
| [1] | Alzheimer A, Forstl H, Levy R. “On certain peculiar diseases of old age.” History of psychiatry” vol. 2(5 Pt 1). 71-101. 1991.View Article PubMed |
| [2] | https://www.alz.org/media/images/2017-facts-and-figures.pdf (Accessed May 2025) |
| [3] | Lupien SJ, Lord C, Sindi S, Wilkinson CW, Fiocco AJ. “Aging and Alzheimer's disease. In R. T. Rubin & D. W. Pfaff (Eds.), Hormone/behavior relations of clinical importance: Endocrine systems interacting with brain and behavior.” Elsevier Academic Press, Cambridge, 2009, 683-714).View Article |
| [4] | Selkoe DJ. “Alzheimer's disease: genes, proteins, and therapy.” Physiological reviews vol. 81(2). 741-766. 2001.View Article PubMed |
| [5] | Ogunmokun G, Dewanjee S, Chakraborty P, Valupadas C, Chaudhary A, Kolli V, et al. “The potential role of cytokines and growth factors in the pathogenesis of Alzheimer’s disease.” Cells vol.10(10). 2790. 2021.View Article PubMed |
| [6] | Reitz C, Mayeux R. “Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers.” Biochemical pharmacology vol. 88(4). 640-651. 2014.View Article PubMed |
| [7] | Hardy J, Selkoe DJ. “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.” Science vol. 297(5580). 353-356. 2002.View Article PubMed |
| [8] | Takahashi RH, Capetillo-Zarate E, Lin MT, et al. “Co-occurrence of Alzheimer's disease β-amyloid and pathologies at synapses.” Neurobiology of aging vol. 31(7). 1145-1152. 2010.View Article PubMed |
| [9] | Kinney JW; Bemiller SM; Murtishaw AS; Leisgang AM.; Salazar AM; Lamb BT. “Inflammation as a central mechanism in Alzheimer’s disease.” Alzheimer’s & dementia vol. 4. 575–590. 2018.View Article PubMed |
| [10] | Rea MI, DS, V, SE, HD, OA. “Age and age-related diseases: role of inflammation triggers and cytokines.” Frontiers in immunology vol. 9(9). 586. 2018.View Article PubMed |
| [11] | Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, et al. “Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.” American journal of human genetics vol. 83(5). 623-632. 2008.View Article PubMed |
| [12] | Agostinho P, Cunha RA, Oliveira C. “Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease.” Currant pharmaceutical design vol. 16(25). 2766-2778. 2010.View Article PubMed |
| [13] | Alasmari F; Alshammari MA; Alasmari AF; Alanazi WA; Alhazzani K. “Neuroinflammatory cytokines induce amyloid beta neurotoxicity through modulating amyloid precursor protein levels/metabolism.” BioMed research international vol. 2018, 3087475. 2018.View Article PubMed |
| [14] | Streit WJ, Mrak RE, Griffin WS. “Microglia and neuroinflammation: a pathological perspective.” Journal of neuroinflammation vol. 1(1). 14. 2004.View Article PubMed |
| [15] | Cameron B, Landreth GE. “Inflammation, microglia, and Alzheimer's disease.” Neurobiological disorders vol. 37(3). 503-509. 2010.View Article PubMed |
| [16] | Taipa R, das Neves SP, Sousa AL, Fernandes J, Pinto C, Correia AP, et al. “Proinflammatory and anti-inflammatory cytokines in the CSF of patients with Alzheimer’s disease and their correlation with cognitive decline.” Neurobiology and aging vol. 76. 125-132. 2019.View Article PubMed |
| [17] | Perry VH, Nicoll JA, Holmes C. “Microglia in neurodegenerative disease.” Nature reviews neurology vol. 6(4). 193-201. 2010.View Article PubMed |
| [18] | Tsai S.J. “Effects of interleukin-1beta polymorphisms on brain function and behavior in healthy and psychiatric disease conditions.” Cytokine & growth factor reviews vol. 37. 89-97. 2017.View Article PubMed |
| [19] | Liu J, Zhao ML, Brosnan CF, Lee SC. “Expression of type II nitric oxide synthase in primary human astrocytes and microglia: Role of IL-1beta and IL-1 receptor antagonist.” Journal of Immunology vol. 157(8). 3569-3576. 1996.View Article PubMed |
| [20] | Niikura T, Tajima H, Kita Y. “Neuronal cell death in Alzheimer’s disease and a neuroprotective factor, humanin.” Current neuropharmacology vol. 4(2). 139-147. 2006.View Article PubMed |
| [21] | Menon PK, Koistinen NA, Iverfeldt K, Ström AL. “Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin.” Journal of biological chemistry vol. 294(47). 17768-17776. 2019.View Article PubMed |
| [22] | Medala VK, Gollapelli B, Dewanjee S, Ogunmokun G, Kandimalla R, Vallamkondu J. “Mitochondrial dysfunction, mitophagy, and role of dynamin-related protein 1 in Alzheimer’s disease.” Journal of neuroscience research vol. 99(4). 1120-1135. 2021.View Article PubMed |
| [23] | Tönnies E, Trushina,E. “Oxidative stress, synaptic dysfunction, and Alzheimer’s disease.” Journal of Alzheimer’s disease vol. 57(4). 1105-1121. 2017.View Article PubMed |
| [24] | Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, et al. “Inflammatory markers and the risk of Alzheimer disease: the Framingham study.” Neurology vol. 68(22). 1902-1908. 2007.View Article PubMed |
| [25] | Gupta A, Pansari K. “Inflammation and Alzheimer's disease.” International journal of clinical practice vol. 57(1). 36-39. 2003.View Article PubMed |
| [26] | Laskowitz DT, Thekdi AD, Thekdi SD, Han SK, Myers JK, Pizzo SV, et al. “Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides.” Experimental neurology vol.167(1). 74-85. 2001.View Article PubMed |
| [27] | Mohit AA, Martin JH, Miller CA. “p493F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system.” Neuron vol. 14. 67-78. 1995.View Article PubMed |
| [28] | Pocivavseka A, Mikhailenko I, Strickland DK, Rebeck GW. “Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation.” Journal of neurology vol. 214(1-2). 25-32. 2009.View Article PubMed |
| [29] | Pocivavsek A, Rebeck GW. “Inhibition of c-Jun N-terminal kinase increases apoE expression in vitro and in vivo.” Biochemical and biophysical research communications vol. 387(3), 516-520. 2009.View Article PubMed |
| [30] | Reynolds CH, Nebreda AR, Gibb GM, Sutton MA, Anderton BH. “Reactivating kinase/p38 phosphorylates protein in vitro.” Journal of neurochemistry vol. 69(1).191-198. 1997.View Article PubMed |
| [31] | Behrens A, Sibilia M, Wagner EF, “Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation.” Nature genetics vol. 21(3). 326-329. 1999.View Article PubMed |
| [32] | Zeke A, Misheva M, Reményi A, Bogoyevitch MA, “JNK Signaling: regulation and functions based on complex protein-protein partnerships.” Microbiology and molecular biology reviews vol. 80(3). 793-835. 2016.View Article PubMed |
| [33] | Tiwari VK, Stadler MB, Wirbelauer C, Paro R, Schübeler D, Beisel C. “A chromatin-modifying function of JNK during stem cell differentiation.” Nature genetics vol. 44(1). 94-100. 2011.View Article PubMed |
| [34] | Zarubin T, Han J. “Activation and signaling of the p38 MAP kinase pathway.” Cell research vol. 15(1). 11-18. 2005.View Article PubMed |
| [35] | Morooka T, Nishida E. “Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells.” Journal of biological chemistry vol. 273(38). 24285-2488. 1998.View Article PubMed |
| [36] | Chun KS, Surh YJ. “Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention.” Biochemical pharmacology vol. 68(6). 1089-100. 2004.View Article PubMed |
| [37] | Fernandez MC, Walters J, Marucha P. “Transcriptional and post-transcriptional regulation of GM-CSF-induced IL-1 beta gene expression in PMN.” Journal of leukocyte biology vol. 59(4). 598-603. 1996.View Article PubMed |
| [38] | Dixon DA, Balch GC, Kedersha N, Anderson P, Zimmerman GA, Beauchamp DR, et al. “Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1.” Journal of exp extramental medicine vol.198(3). 475-81. 2003.View Article PubMed |
| [39] | Cvoro A, Yuan C, Paruthiyil S, Miller OH, Yamamoto KR, Leitman DC. “Cross talk between glucocorticoid and estrogen receptors occurs at a subset of proinflammatory genes.” Journal of immunology vol. 186(7). 4354-4360. 2011.View Article PubMed |
| [40] | Lopez G, Goc A, Rath M, Niedzwiecki A. “Natural compounds modulate apolipoprotein E gene and protein expression in fibroblasts derived from young and old female Alzheimer’s patients.” American journal of food and nutrition vol. 12(2). 49-58. 2024.View Article |
| [41] | Olesen, M.A., Villavicencio-Tejo, F. & Quintanilla, R.A. The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders. Transl Neurodegener 11, 36 (2022). https://doi.org/10.1186/s40035-022-00308-y |
| [42] | Rossi A, Rigotto G, Valente G, Giorgio V, Basso E, Filadi R, et al. “Defective mitochondrial pyruvate flux affects cell bioenergetics in Alzheimer's disease-related models.” Cell reports vol. 30(7). 2332-2348. 2020.View Article PubMed |
| [43] | Mendonsa G, Dobrowolska J, Lin A, Vijairania P, Jong YJ, Baenziger NL. “Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts.” PloS one vol. 4(2). e4655. 2009.View Article PubMed |
| [44] | Livak KJ, Schmittgen TD. “Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.” Methods (San Diego, Calif.) vol. 25(4). 402-408. 2001.View Article PubMed |
| [45] | Carlberg C, Raczyk M, Zawrotna N. “Vitamin D: a master example of nutrigenomics.” Redox biology vol. 62. 102695. 2023.View Article PubMed |
| [46] | Jiang Y, Gong P, Madak-Erdogan Z, Martin T, Jeyakumar M, Carlson K, et al. “Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens.” FASEB vol. 27(11). 4406-18. 2013.View Article PubMed |
| [47] | Saito K, Cui H. “Estrogen receptor alpha splice variants, post-translational modifications, and their physiological functions. Cells vol. 12(6). 895. 2023.View Article PubMed |
| [48] | Ajit R, Srivastava K, Srivastava N, Averna M, Lin RC, Korach KS, et. Al. “Estrogen up-regulates Aapolipoprotein E (ApoE) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor α-mediated pathway.” Journal of biological chemistry vol. 272(52). 33360-33366. 1997.View Article PubMed |
| [49] | Chen Y, Yu Y. “Tau and neuroinflammation in Alzheimer's disease: interplay mechanisms and clinical translation.” Journal of neuroinflammation vol. 20(1). 165. 2023.View Article PubMed |
| [50] | Laske C, Stellos K, Stransky E, Leyhe T, Gawaz M. “Decreased plasma levels of granulocyte-colony stimulating factor (G-CSF) in patients with early Alzheimer's disease.” Journal of Alzheimer’s disease vol. 17(1). 115-123. 2009.View Article PubMed |
| [51] | Coward WR, Feghali-Bostwick CA, Jenkins G, Knox AJ, Pang L. “A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis.” FASEB vol. 28(7). 3183-3196. 2014.View Article PubMed |
| [52] | Gorzkiewicz J, Bartosz G, Sadowska-Bartosz I. “The potential effects of phytoestrogens: the role in neuroprotection.” Molecules vol. 26(10). 2954-2966. 2021.View Article PubMed |
| [53] | Antoon JW, Meacham WD, Bratton MR, Slaughter EM, Rhodes LV, Ashe HB, et al. “Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer.” Journal of molecular endocrinology vol. 46(3). 205-216. 2011.View Article PubMed |
| [54] | Qi X, Tang J, Pramanik R, Schultz RM, Shirasawa S, Sasazuki T, et al. “p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor.” Journal of biological chemistry vol. 279(21). 22138-22144. 2004.View Article PubMed |
| [55] | Bekic S, Petri E, Krstić S, Ćelić A, Jovanović-Šanta S. “Detection of isoflavones and phytoestrogen-rich plant extracts binding to estrogen receptor β using a yeast-based fluorescent assay.” Analytical biochemistry vol. 690. 115529. 2024.View Article PubMed |
| [56] | Danciu C, Avram S, Pavel IZ, Ghiulai R, Dehelean CA, Ersilia A, et al. “Main isoflavones found in dietary sources as natural anti-inflammatory agents.” Current drug targets vol. 19(7). 841-853. 2018.View Article PubMed |
| [57] | Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. “Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.” Endocrinology vol. 139(10). 4252-63. 1998.View Article PubMed |
| [58] | Arterburn JB, Prossnitz ER. “G Protein-Coupled Estrogen Receptor GPER: Molecular pharmacology and therapeutic applications.” Annual review of pharmacology and toxicology vol. 63. 295-320. 2023.View Article PubMed |
| [59] | Marino M, Ascenzi P, Acconcia F. “S-palmitoylation modulates estrogen receptor alpha localization and functions.” Steroids vol. 71(4). 298-303. 2006.View Article PubMed |
| [60] | Chen B, Gajdos C, Dardes R, Kidwai N, Johnston SRD, Dowsett M, et al. “Potential of endogenous estrogen receptor beta to influence the selective ER modulator ERbeta complex.” International journal of oncology vol. 27(2). 327-235. 2005.View Article |
| [61] | Kurzer MS, Xu X. “Dietary phytoestrogens.” Annuals review of nutrition vol. 17. 353-381. 1997.View Article PubMed |
| [62] | Maharjan CK, Mo J, Wang L, Kim M, Wang S, Borcherding N, et al. “Natural and synthetic estrogens in chronic inflammation and breast cancer.” Cancers vol. 14(1). 206. 2022.View Article PubMed |
| [63] | Sato K, Takayama KI, Inoue S. “Expression and function of estrogen receptors and estrogen-related receptors in the brain and their association with Alzheimer's disease.” Frontiers of endocrinology (Lausanne) vol. 14. 1220150. 2023.View Article PubMed |
| [64] | Yore MA, Im D, Webb LK, Zhao Y, Chadwick Jr JG, Molenda-Figueira HA, Haidacher SJ, et al. “Steroid receptor coactivator-2 expression in brain and physical associations with steroid receptors.” Neuroscience vol. 169(3). 1017-1028. 2010.View Article PubMed |
