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• W2904678448 abstract "“Nutraceuticals” are well-tolerated natural dietary compounds with drug-like properties that make them attractive as Alzheimer's disease (AD) therapeutics. Combination therapy for AD has garnered attention following a recent National Institute on Aging mandate, but this approach has not yet been fully validated. In this report, we combined the two most promising nutraceuticals with complementary anti-amyloidogenic properties: the plant-derived phenolics (−)-epigallocatechin-3-gallate (EGCG, an α-secretase activator) and ferulic acid (FA, a β-secretase modulator). We used transgenic mice expressing mutant human amyloid β-protein precursor and presenilin 1 (APP/PS1) to model cerebral amyloidosis. At 12 months of age, we orally administered EGCG and/or FA (30 mg/kg each) or vehicle once daily for 3 months. At 15 months, combined EGCG–FA treatment reversed cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks. Moreover, EGCG- and FA-treated APP/PS1 mice exhibited amelioration of brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-proteins compared with either EGCG or FA single treatment. Combined treatment elevated nonamyloidogenic soluble APP-α and α-secretase candidate and down-regulated amyloidogenic soluble APP-β, β-C-terminal APP fragment, and β-secretase protein expression, providing evidence for a shift toward nonamyloidogenic APP processing. Additional beneficial co-treatment effects included amelioration of neuroinflammation, oxidative stress, and synaptotoxicity. Our findings offer preclinical evidence that combined treatment with EGCG and FA is a promising AD therapeutic approach. “Nutraceuticals” are well-tolerated natural dietary compounds with drug-like properties that make them attractive as Alzheimer's disease (AD) therapeutics. Combination therapy for AD has garnered attention following a recent National Institute on Aging mandate, but this approach has not yet been fully validated. In this report, we combined the two most promising nutraceuticals with complementary anti-amyloidogenic properties: the plant-derived phenolics (−)-epigallocatechin-3-gallate (EGCG, an α-secretase activator) and ferulic acid (FA, a β-secretase modulator). We used transgenic mice expressing mutant human amyloid β-protein precursor and presenilin 1 (APP/PS1) to model cerebral amyloidosis. At 12 months of age, we orally administered EGCG and/or FA (30 mg/kg each) or vehicle once daily for 3 months. At 15 months, combined EGCG–FA treatment reversed cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks. Moreover, EGCG- and FA-treated APP/PS1 mice exhibited amelioration of brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-proteins compared with either EGCG or FA single treatment. Combined treatment elevated nonamyloidogenic soluble APP-α and α-secretase candidate and down-regulated amyloidogenic soluble APP-β, β-C-terminal APP fragment, and β-secretase protein expression, providing evidence for a shift toward nonamyloidogenic APP processing. Additional beneficial co-treatment effects included amelioration of neuroinflammation, oxidative stress, and synaptotoxicity. Our findings offer preclinical evidence that combined treatment with EGCG and FA is a promising AD therapeutic approach. Largely because of significant increases in life span, Alzheimer's disease (AD) 3The abbreviations used are: ADAlzheimer's diseaseAβamyloid β-proteinAPPamyloid β-protein precursorsAPP-αsoluble APP-αEGCG(−)-epigallocatechin-3-gallateFAferulic acidADAM10a disintegrin and metalloproteinase domain-containing protein 10APP/PS1the mutant human APP and presenilin 1APP/PS1 miceAPP/PS1 transgenic mouse model of cerebral amyloidosisRAWMradial arm water mazeANOVAanalysis of varianceRSCretrosplenial cortexECentorhinal cortexHhippocampusROIregions of interestCAAcerebral amyloid angiopathysAPP-βsoluble APP-ββ-CTF/C99β-C-terminal APP fragmentP-β-CTF/P-C99phospho-β-CTFBACE1β-site APP-cleaving enzyme 1pADAM10precursor ADAM10mADAM10mature (active) ADAM10TNF-αtumor necrosis factor-αIL-1βinterleukin-1βSOD1superoxide dismutase 1GPx1GSH peroxidase 1QPCRquantitative real-time PCRGFAPglial fibrillary acidic proteinIba1ionized calcium-binding adapter molecule 1IRimmunoreactivityLD50lethal dose for 50% survival. has become a worldwide public health concern. AD is a fatal neurodegenerative illness that likely begins with brain changes 20 years or more prior to clinical symptoms. AD is characterized by progressive decline in memory and other cognitive functions, eventually leading to dementia and death. Neuropathological hallmarks of AD include extracellular senile plaques and intracellular neurofibrillary tangles, accompanied by neuroinflammation, synaptic toxicity, and neuron loss (1Selkoe D.J. Alzheimer's disease: genes, proteins, and therapy.Physiol. Rev. 2001; 81 (11274343): 741-76610.1152/physrev.2001.81.2.741Crossref PubMed Scopus (5156) Google Scholar). Amyloid β-protein (Aβ), a peptide derived from amyloid β-protein precursor (APP), has garnered major interest as a therapeutic target for AD. Two enzymes, the β- and γ-secretases, cleave APP into smaller amyloidogenic peptides: Aβ(1–40) and Aβ(1–42), which can form both oligomeric and multimeric aggregates (2De Strooper B. Saftig P. Craessaerts K. Vanderstichele H. Guhde G. Annaert W. Von Figura K. Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.Nature. 1998; 391 (9450754): 387-39010.1038/34910Crossref PubMed Scopus (1548) Google Scholar3Sinha S. Lieberburg I. Cellular mechanisms of β-amyloid production and secretion.Proc. Natl. Acad. Sci. U.S.A. 1999; 96 (10500121): 11049-1105310.1073/pnas.96.20.11049Crossref PubMed Scopus (425) Google Scholar, 4Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. et al.β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.Science. 1999; 286 (10531052): 735-74110.1126/science.286.5440.735Crossref PubMed Scopus (3299) Google Scholar5Kimberly W.T. LaVoie M.J. Ostaszewski B.L. Ye W. Wolfe M.S. Selkoe D.J. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.Proc. Natl. Acad. Sci. U.S.A. 2003; 100 (12740439): 6382-638710.1073/pnas.1037392100Crossref PubMed Scopus (676) Google Scholar). Once cleaved from APP, Aβ enters into systemic equilibrium between soluble and deposited forms (6DeMattos R.B. Bales K.R. Cummins D.J. Paul S.M. Holtzman D.M. Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease.Science. 2002; 295 (11910111): 2264-226710.1126/science.1067568Crossref PubMed Scopus (516) Google Scholar). Conversely, nonamyloidogenic α-secretase cleavage of APP precludes Aβ formation and produces soluble APP-α (sAPP-α) (3Sinha S. Lieberburg I. Cellular mechanisms of β-amyloid production and secretion.Proc. Natl. Acad. Sci. U.S.A. 1999; 96 (10500121): 11049-1105310.1073/pnas.96.20.11049Crossref PubMed Scopus (425) Google Scholar, 7Postina R. Schroeder A. Dewachter I. Bohl J. Schmitt U. Kojro E. Prinzen C. Endres K. Hiemke C. Blessing M. Flamez P. Dequenne A. Godaux E. van Leuven F. Fahrenholz F. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model.J. Clin. Invest. 2004; 113 (15146243): 1456-146410.1172/JCI20864Crossref PubMed Scopus (527) Google Scholar). Because the nonamyloidogenic pathway is the homeostatic default, this results in constitutively low Aβ levels. Alzheimer's disease amyloid β-protein amyloid β-protein precursor soluble APP-α (−)-epigallocatechin-3-gallate ferulic acid a disintegrin and metalloproteinase domain-containing protein 10 the mutant human APP and presenilin 1 APP/PS1 transgenic mouse model of cerebral amyloidosis radial arm water maze analysis of variance retrosplenial cortex entorhinal cortex hippocampus regions of interest cerebral amyloid angiopathy soluble APP-β β-C-terminal APP fragment phospho-β-CTF β-site APP-cleaving enzyme 1 precursor ADAM10 mature (active) ADAM10 tumor necrosis factor-α interleukin-1β superoxide dismutase 1 GSH peroxidase 1 quantitative real-time PCR glial fibrillary acidic protein ionized calcium-binding adapter molecule 1 immunoreactivity lethal dose for 50% survival. Despite intense investigation, a synthetic drug that is both safe and effective has not yet been developed for AD. This inconvenient truth has led to the consideration of alternative strategies, including naturally occurring dietary compounds with therapeutic potential (so-called “nutraceuticals”). Another important matter is a recent mandate to develop combination therapy for AD. Because nutraceuticals are generally safe and well-tolerated, these agents are more amenable to combination than designer drugs. In this report, we explore combination therapy with two promising nutraceuticals that have complementary anti-amyloidogenic properties: (−)-epigallocatechin-3-gallate (EGCG, an α-secretase enhancer) (8Rezai-Zadeh K. Shytle D. Sun N. Mori T. Hou H. Jeanniton D. Ehrhart J. Townsend K. Zeng J. Morgan D. Hardy J. Town T. Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.J. Neurosci. 2005; 25 (16177050): 8807-881410.1523/JNEUROSCI.1521-05.2005Crossref PubMed Scopus (582) Google Scholar, 9Obregon D.F. Rezai-Zadeh K. Bai Y. Sun N. Hou H. Ehrhart J. Zeng J. Mori T. Arendash G.W. Shytle D. Town T. Tan J. ADAM10 activation is required for green tea (−)-epigallocatechin-3-gallate–induced α-secretase cleavage of amyloid precursor protein.J. Biol. Chem. 2006; 281 (16624814): 16419-1642710.1074/jbc.M600617200Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar) and ferulic acid (FA, a β-secretase modulator) (10Mori T. Koyama N. Guillot-Sestier M.V. Tan J. Town T. Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice.PLoS ONE. 2013; 8 (23409038)e5577410.1371/journal.pone.0055774Crossref PubMed Scopus (149) Google Scholar). EGCG is a polyphenol catechin (the ester of epigallocatechin and gallic acid) (11Legeay S. Rodier M. Fillon L. Faure S. Clere N. Epigallocatechin gallate: a review of its beneficial properties to prevent metabolic syndrome.Nutrients. 2015; 7 (26198245): 5443-546810.3390/nu7075230Crossref PubMed Scopus (192) Google Scholar) that is found in high abundance in tea leaves, including green tea, and in carob flour (i.e. Ceratonia siliqua) at lesser abundance. Trace amounts are found in fruits (e.g. apple and cranberries) and nuts (e.g. pecans and hazelnuts) (12Harnly J.M. Doherty R.F. Beecher G.R. Holden J.M. Haytowitz D.B. Bhagwat S. Gebhardt S. Flavonoid content of U.S. fruits, vegetables, and nuts.J. Agric. Food Chem. 2006; 54 (17177529): 9966-997710.1021/jf061478aCrossref PubMed Scopus (390) Google Scholar) (http://www.ars.usda.gov/nutrientdata). 4Please note that the JBC is not responsible for the long-term archiving and maintenance of this site or any other third party hosted site. EGCG has garnered attention as a medicinal agent to improve cognition, reduce inflammation, and even to treat cancer. Beneficial effects are often attributed to anti-oxidant, metal-chelating, anti-inflammatory, anti-carcinogenic, and anti-apoptotic properties (13Singh N.A. Mandal A.K. Khan Z.A. Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG).Nutr. J. 2016; 15 (27268025): 6010.1186/s12937-016-0179-4Crossref PubMed Scopus (161) Google Scholar). Substantial quantities pass from the small to the large intestine, where EGCG undergoes degradation by gut flora and absorption. EGCG can be reabsorbed from the intestine through enterohepatic re-circulation (14Lee M.J. Maliakal P. Chen L. Meng X. Bondoc F.Y. Prabhu S. Lambert G. Mohr S. Yang C.S. Pharmacokinetics of tea catechins after ingestion of green tea and (−)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability.Cancer Epidemiol. Biomarkers Prev. 2002; 11 (12376503): 1025-1032PubMed Google Scholar, 15van't Slot G. Humpf H.U. Degradation and metabolism of catechin, epigallocatechin-3-gallate (EGCG), and related compounds by the intestinal microbiota in the pig cecum model.J. Agric. Food Chem. 2009; 57 (19670865): 8041-804810.1021/jf900458eCrossref PubMed Scopus (81) Google Scholar). It has been shown that EGCG crosses the blood–brain barrier after systemic administration (16Lin L.C. Wang M.N. Tseng T.Y. Sung J.S. Tsai T.H. Pharmacokinetics of (−)-epigallocatechin-3-gallate in conscious and freely moving rats and its brain regional distribution.J. Agric. Food Chem. 2007; 55 (17256961): 1517-152410.1021/jf062816aCrossref PubMed Scopus (171) Google Scholar), and we were the first to show that EGCG enhances APP cleavage to sAPP-α and reduces Aβ abundance both in neuron-like cells and in Tg2576 mouse brains (8Rezai-Zadeh K. Shytle D. Sun N. Mori T. Hou H. Jeanniton D. Ehrhart J. Townsend K. Zeng J. Morgan D. Hardy J. Town T. Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.J. Neurosci. 2005; 25 (16177050): 8807-881410.1523/JNEUROSCI.1521-05.2005Crossref PubMed Scopus (582) Google Scholar). A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) activation is mechanistically responsible for EGCG promotion of nonamyloidogenic α-secretase APP cleavage (9Obregon D.F. Rezai-Zadeh K. Bai Y. Sun N. Hou H. Ehrhart J. Zeng J. Mori T. Arendash G.W. Shytle D. Town T. Tan J. ADAM10 activation is required for green tea (−)-epigallocatechin-3-gallate–induced α-secretase cleavage of amyloid precursor protein.J. Biol. Chem. 2006; 281 (16624814): 16419-1642710.1074/jbc.M600617200Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). Like EGCG, FA is also a plant-derived compound. Seed plants and leaves (e.g. rice, wheat, and oats), vegetables (e.g. tomatoes and carrots), and fruits (e.g. pineapples and oranges) are the main sources of dietary FA. The compound has both anti-inflammatory and anti-oxidant properties (10Mori T. Koyama N. Guillot-Sestier M.V. Tan J. Town T. Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice.PLoS ONE. 2013; 8 (23409038)e5577410.1371/journal.pone.0055774Crossref PubMed Scopus (149) Google Scholar, 17Kanski J. Aksenova M. Stoyanova A. Butterfield D.A. Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: structure-activity studies.J. Nutr. Biochem. 2002; 13 (12015157): 273-28110.1016/S0955-2863(01)00215-7Crossref PubMed Scopus (433) Google Scholar, 18Srinivasan M. Sudheer A.R. Menon V.P. Ferulic acid: therapeutic potential through its antioxidant property.J. Clin. Biochem. Nutr. 2007; 40 (18188410): 92-10010.3164/jcbn.40.92Crossref PubMed Scopus (724) Google Scholar), and we have previously shown that FA is a β-secretase modulator that inhibits amyloidogenic APP cleavage. We further reported that FA reverses cognitive/behavioral deficits and mitigates AD-like pathology after 6 months of oral treatment in a transgenic mouse model of cerebral amyloidosis, and it alters amyloidogenic β-secretase APP cleavage in mutant APP-overexpressing neuron-like cells (10Mori T. Koyama N. Guillot-Sestier M.V. Tan J. Town T. Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice.PLoS ONE. 2013; 8 (23409038)e5577410.1371/journal.pone.0055774Crossref PubMed Scopus (149) Google Scholar). Because FA has a relatively low molecular weight, the compound is freely cell-permeable and bioavailable. FA is absorbed in free form via stomach mucosa and is then transported into the hepatic portal vein where it is metabolized in the liver. Of note, oral FA can be recovered in rat plasma after only 5 min, when the ratio of free FA to total FA is markedly increased, but it rapidly gives rise to conjugated FA. Both free and conjugated FA are distributed via the systemic circulation into peripheral tissues (18Srinivasan M. Sudheer A.R. Menon V.P. Ferulic acid: therapeutic potential through its antioxidant property.J. Clin. Biochem. Nutr. 2007; 40 (18188410): 92-10010.3164/jcbn.40.92Crossref PubMed Scopus (724) Google Scholar, 19Zhao Z. Egashira Y. Sanada H. Ferulic acid is quickly absorbed from rat stomach as the free form and then conjugated mainly in liver.J. Nutr. 2004; 134 (15514279): 3083-308810.1093/jn/134.11.3083Crossref PubMed Scopus (173) Google Scholar20Zhao Z. Moghadasian M.H. Chemistry, natural sources, dietary intake and pharmacokinetic properties of ferulic acid: a review.Food Chem. 2008; 109 (26049981): 691-70210.1016/j.foodchem.2008.02.039Crossref PubMed Scopus (460) Google Scholar). Whereas FA is negatively charged at physiological pH due to a hydroxyl moiety (21Sultana R. Ravagna A. Mohmmad-Abdul H. Calabrese V. Butterfield D.A. Ferulic acid ethyl ester protects neurons against amyloid β-peptide(1–42)-induced oxidative stress and neurotoxicity: relationship to antioxidant activity.J. Neurochem. 2005; 92 (15686476): 749-75810.1111/j.1471-4159.2004.02899.xCrossref PubMed Scopus (249) Google Scholar), the compound has been shown to cross the blood–brain barrier in rodents after peripheral administration (22Qin J. Chen D. Lu W. Xu H. Yan C. Hu H. Chen B. Qiao M. Zhao X. Preparation, characterization, and evaluation of liposomal ferulic acid in vitro and in vivo.Drug Dev. Ind. Pharm. 2008; 34: 602-60810.1080/03639040701833559Crossref PubMed Scopus (24) Google Scholar, 23Wu K. Wang Z.Z. Liu D. Qi X.R. Pharmacokinetics, brain distribution, release and blood–brain barrier transport of Shunaoxin pills.J. Ethnopharmacol. 2014; 151 (24373808): 1133-114010.1016/j.jep.2013.12.027Crossref PubMed Scopus (32) Google Scholar). Given that both compounds share anti-inflammatory and anti-oxidant properties and have complementary modes of action on APP cleavage, we tested whether combination therapy with EGCG and FA (each at 30 mg/kg) ameliorated learning and memory changes, cerebral amyloidosis, AD-like pathology, and amyloidogenic APP processing in the mutant human APP and presenilin 1 (APP/PS1) transgenic mouse model of cerebral amyloidosis (APP/PS1 mice). We orally administered EGCG/FA (alone or in combination) or vehicle to APP/PS1 mice once daily for 3 months (beginning at 12 months of age) and evaluated animals at 15 months old. Here, our pre-clinical results show that combination therapy with EGCG plus FA has significant advantages over single treatment with either compound. APP/PS1 mice reportedly have transgene-associated behavioral impairment as early as 5–7 months of age (24Arendash G.W. King D.L. Gordon M.N. Morgan D. Hatcher J.M. Hope C.E. Diamond D.M. Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes.Brain Res. 2001; 891 (11164808): 42-5310.1016/S0006-8993(00)03186-3Crossref PubMed Scopus (287) Google Scholar), so we began by assessing baseline cognitive status prior to dosing at 12 months. Data revealed behavioral impairment in novel object recognition, Y-maze, and radial arm water maze (RAWM) tests in our cohort of 12-month-old APP/PS1 mice versus wildtype (WT) littermate controls (data not shown). We then randomly assigned behaviorally impaired APP/PS1 mice (four treatments with n = 8 per group; equal numbers of four males and four females) and WT littermates (same group sizes and distribution as APP/PS1 mice). Single or double treatment (via gavage using a 6202 gastric tube with a rounded silicone-coated tip, Fuchigami Kikai, Kyoto, Japan) was given once daily for 3 months with EGCG and/or FA (each at 30 mg/kg) or vehicle beginning at 12 months in APP/PS1 and in WT littermate controls. This directly administered treatment more precisely delivers the targeted amount of agent compared with ad libitum access to drinking water or chow. At the end of treatment (15 months of age), we conducted a behavioral testing battery. We initially assessed episodic memory by novel object recognition test, and all eight mouse groups showed similar recognition indices (50.3–52.5%) in the training phase of the test (Fig. 1A, left; Table S1). In the retention phase, one-way analysis of variance (ANOVA) followed by post hoc comparison disclosed statistically significant differences on recognition index between APP/PS1-V mice and the other seven mouse groups (Fig. 1A, right; Table S1; *, p < 0.05 for APP/PS1-V versus all other mouse groups). Singly- or doubly-treated APP/PS1 mice had significantly increased novel object exploration frequency by 60.8–71.6% versus APP/PS1-V mice (50.0%). Of note, EGCG/FA combination therapy completely mitigated episodic memory impairment (Fig. 1A, right; Table S1; †, p < 0.05, APP/PS1-EGCG/FA versus APP/PS1-EGCG or APP/PS1-FA mice), as there were no significant differences versus any of the WT mouse groups (Fig. 1A, right; Table S1; p > 0.05). We moved on to test exploratory activity and spatial working memory in the alternation Y-maze task. One-way ANOVA followed by post hoc testing revealed statistically significant differences for total arm entries between APP/PS1-V mice and the other seven mouse groups (Fig. 1B, left; Table S2; *, p < 0.05). This transgene-related behavioral phenotype has been noted in this and other mouse models of cerebral amyloidosis (10Mori T. Koyama N. Guillot-Sestier M.V. Tan J. Town T. Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice.PLoS ONE. 2013; 8 (23409038)e5577410.1371/journal.pone.0055774Crossref PubMed Scopus (149) Google Scholar, 24Arendash G.W. King D.L. Gordon M.N. Morgan D. Hatcher J.M. Hope C.E. Diamond D.M. Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes.Brain Res. 2001; 891 (11164808): 42-5310.1016/S0006-8993(00)03186-3Crossref PubMed Scopus (287) Google Scholar25King D.L. Arendash G.W. Crawford F. Sterk T. Menendez J. Mullan M.J. Progressive and gender-dependent cognitive impairment in the APPSW transgenic mouse model for Alzheimer's disease.Behav. Brain Res. 1999; 103 (10513583): 145-16210.1016/S0166-4328(99)00037-6Crossref PubMed Scopus (198) Google Scholar, 26Town T. Laouar Y. Pittenger C. Mori T. Szekely C.A. Tan J. Duman R.S. Flavell R.A. Blocking TGF-β-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology.Nat. Med. 2008; 14 (18516051): 681-68710.1038/nm1781Crossref PubMed Scopus (363) Google Scholar, 27Mori T. Rezai-Zadeh K. Koyama N. Arendash G.W. Yamaguchi H. Kakuda N. Horikoshi-Sakuraba Y. Tan J. Town T. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice.J. Biol. Chem. 2012; 287 (22219198): 6912-692710.1074/jbc.M111.294025Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar28Mori T. Koyama N. Segawa T. Maeda M. Maruyama N. Kinoshita N. Hou H. Tan J. Town T. Methylene blue modulates β-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice.J. Biol. Chem. 2014; 289 (25157105): 30303-3031710.1074/jbc.M114.568212Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), and it may mirror disinhibition caused by cortical and/or hippocampal damage (29Kim K.S. Han P.L. Optimization of chronic stress paradigms using anxiety- and depression-like behavioral parameters.J. Neurosci. Res. 2006; 83 (16416425): 497-50710.1002/jnr.20754Crossref PubMed Scopus (148) Google Scholar). Of interest, APP/PS1 transgene-associated hyperactivity, often taken as anxiety-like behavior in APP/PS1 mice, was completely reversed by combined treatment with EGCG plus FA (Fig. 1B, left; Table S2; †, p < 0.05, APP/PS1-EGCG/FA versus APP/PS1-EGCG or APP/PS1-FA mice). Combination treatment completely stabilized hyperactivity, as the co-treatment group did not significantly differ from any of the WT mouse groups (Fig. 1B, left; Table S2; p > 0.05). Mice instinctively alternate arms in the Y-maze, such that they enter the three arms in sequence more often than by chance alone (50%, see dotted line in Fig. 1B, right; Table S2); this behavioral phenotype is generally interpreted as a measure of spatial working memory (24Arendash G.W. King D.L. Gordon M.N. Morgan D. Hatcher J.M. Hope C.E. Diamond D.M. Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes.Brain Res. 2001; 891 (11164808): 42-5310.1016/S0006-8993(00)03186-3Crossref PubMed Scopus (287) Google Scholar). As expected, APP/PS1-V mouse behavior revealed less tendency to alternate versus WT controls. One-way ANOVA followed by post hoc testing showed statistically significant differences on Y-maze spontaneous alternation between APP/PS1-V mice and the other seven mouse groups (Fig. 1B, right; Table S2; *, p < 0.05). Of note, EGCG- plus FA-treated APP/PS1 mice had greater % alternation compared with EGCG or FA single treatment (Fig. 1B, right; Table S2; ††, p < 0.01, APP/PS1-EGCG/FA versus APP/PS1-EGCG or APP/PS1-FA mice), which did not significantly differ from any of the WT mouse groups (Fig. 1B, right; Table S2; p > 0.05). Therefore, combination treatment fully restored defective spatial working memory in the alternation Y-maze. Finally, we assessed hippocampus-dependent spatial reference learning and memory with the RAWM test. On day 1, overall ANOVA disclosed the main effects of block (p < 0.001 for both errors and escape latency), genotype (p < 0.05 for errors and p < 0.01 for escape latency), and treatment (p < 0.05 for escape latency). APP/PS1-V mice tended toward increased number of errors and longer escape latencies to reach the visible or hidden platform locations compared with the other seven mouse groups. On day 2, overall ANOVA revealed the main effects of block (p < 0.001 for both errors and escape latency), genotype (p < 0.05 for errors and p < 0.01 for escape latency), and treatment (p < 0.001 for both errors and escape latency). Repeated-measures ANOVA followed by post hoc assessment disclosed statistically significant differences between APP/PS1-V mice and the other seven mouse groups (Fig. 1, C and D, left; Tables S3 and S5; *, p < 0.05 for both errors and escape latency). APP/PS1-V mice had more errors and greater escape latencies to reach the visible or hidden platforms compared with the other seven mouse groups; yet, either singly- or doubly-treated APP/PS1 mice accomplished the task with significantly less errors and shorter latencies, and their behavior did not significantly differ from the four WT mouse groups (Fig. 1, C and D, left and right; Tables S3–S6; p > 0.05). There were no significant between-group differences (p > 0.05) on swim speed, nor did we find thigmotaxis (characteristic of extreme anxiety-like behavior) in any of the mice tested. Thus, behavioral differences in the RAWM test were not due to motivational issues, locomotor impairment, or anxiety. These results show that the 3-month treatment with EGCG and/or FA completely remediates spatial reference learning and memory impairment associated with the APP and PS1 transgenes. For all behavioral tests, sex was included as a categorical covariate in multiple ANOVA models, but we did not find significant main effects or interactive terms with sex (p > 0.05). Furthermore, we stratified all analyses by sex and did not find any significant differences (p > 0.05; data not shown). At 15 months of age, APP/PS1-V mice had progressive cerebral amyloid pathology (average of 7–8% cerebral β-amyloid burden) throughout the retrosplenial cortex (RSC), entorhinal cortex (EC), and hippocampus (H) regions of interest (ROI). Treatment with EGCG (32–40%) or FA (29–35%) significantly reduced β-amyloid burden (by Aβ(17–24) mAb 4G8) across all three brain regions (Figs. 2, A–D, and 3, A–C; ***, p ≤ 0.001). Importantly, combination therapy with EGCG plus FA further significantly mitigated cerebral amyloidosis in all three brain regions (50–60%) (Fig. 3, A–C; †, p < 0.05). To further examine whether the 3-month treatment prevented versus reversed cerebral β-amyloid deposition, we included a separate cohort of eight untreated 12-month-old APP/PS1 mice (the age when dosing started) in the analysis (Fig. 3, A–C). Intriguingly, combined treatment trended toward reversing cerebral amyloid pathology across all three brain regions (Fig. 3, A–C). This effect was sex-independent (data not shown).Figure 3Combined treatment with EGCG plus FA effectively attenuates cerebral parenchymal and vascular β-amyloid deposits and lowers Aβ levels. A–C, quantitative image analysis of Aβ burden (%) from 4G8 immunostains is shown. D–F, morphometric analysis of cerebral parenchymal β-amyloid deposit size. Mean plaque size is shown from blind assignment to one of three mutually exclusive categories: small (<25 μm; D), medium (between 25 and 50 μm; E), or large (>50 μm; F). G, severity of cerebral amyloid angiopathy (mean CAA deposit number) is shown. A–C, each brain region is indicated on the x axis (RSC, H, and EC). D–F, mean deposit number is shown on the y axis, and brain region is denoted on the x axis. G, mean CAA number is shown on the y axis, and brain region is presented on the x axis. Dat" @default.
• W2904678448 created "2018-12-22" @default.
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• W2904678448 date "2019-02-01" @default.
• W2904678448 modified "2023-10-16" @default.
• W2904678448 title "Combined treatment with the phenolics (−)-epigallocatechin-3-gallate and ferulic acid improves cognition and reduces Alzheimer-like pathology in mice" @default.
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• W2904678448 doi "https://doi.org/10.1074/jbc.ra118.004280" @default.
• W2904678448 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6393618" @default.
• W2904678448 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30563837" @default.
• W2904678448 hasPublicationYear "2019" @default.
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