{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:22:41Z","timestamp":1760239361638,"version":"build-2065373602"},"reference-count":82,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,23]],"date-time":"2020-10-23T00:00:00Z","timestamp":1603411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MEDICE Arzneimittel P\u00fctter GmbH &amp; Co. KG","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer\u2019s disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. Methods: Urine and serum samples were analyzed using a validated LC-MS\/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-\u03b2 (A\u03b2) plaque deposition. Results: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL\/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified A\u03b2 plaque deposition in 35-week-old AppNL-G-F mice. Conclusion: Despite prominent A\u03b2 plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.<\/jats:p>","DOI":"10.3390\/nu12113248","type":"journal-article","created":{"date-parts":[[2020,10,23]],"date-time":"2020-10-23T08:59:28Z","timestamp":1603443568000},"page":"3248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Impact of Hyperhomocysteinemia and Different Dietary Interventions on Cognitive Performance in a Knock-in Mouse Model for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-6312","authenticated-orcid":false,"given":"Hendrik","family":"Nieraad","sequence":"first","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2456-2783","authenticated-orcid":false,"given":"Natasja","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-5849","authenticated-orcid":false,"given":"Olga","family":"Arne","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8280-2036","authenticated-orcid":false,"given":"Martine C. J.","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mike","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-9251","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan"},{"name":"Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8218-1295","authenticated-orcid":false,"given":"Robert","family":"Gurke","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"},{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institute of Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uwe","family":"Till","sequence":"additional","affiliation":[{"name":"Former Institute of Pathobiochemistry, Friedrich-Schiller-University Jena, Nonnenplan 2, 07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Parnham","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerd","family":"Geisslinger","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"},{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institute of Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,23]]},"reference":[{"key":"ref_1","unstructured":"(2019). World Alzheimer Report 2019: Attitudes to Dementia, Alzheimer\u2019s Disease International."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.3389\/fphar.2019.01465","article-title":"The Use of Antipsychotic Drugs for Treating Behavioral Symptoms in Alzheimer\u2019s Disease","volume":"10","author":"Calsolaro","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e201797397","DOI":"10.15252\/embj.201797397","article-title":"APP mouse models for Alzheimer\u2019s disease preclinical studies","volume":"36","author":"Sasaguri","year":"2017","journal-title":"EMBO J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1212\/WNL.0000000000006745","article-title":"Translating the biology of aging into novel therapeutics for Alzheimer disease","volume":"92","author":"Hara","year":"2019","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.pneurobio.2018.12.006","article-title":"Comprehensive review of mechanisms of pathogenesis involved in Alzheimer\u2019s disease and potential therapeutic strategies","volume":"174","author":"Sharma","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","article-title":"Amyloid plaque core protein in Alzheimer disease and Down syndrome","volume":"82","author":"Masters","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Selkoe, D.J., and Hardy, J. (2016). The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. EMBO Mol. Med.","DOI":"10.15252\/emmm.201606210"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and Biomarker Changes in Dominantly Inherited Alzheimer\u2019s Disease","volume":"367","author":"Bateman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nn.3697","article-title":"Single App knock-in mouse models of Alzheimer\u2019s disease","volume":"17","author":"Saito","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2018.01070","article-title":"Betaine in Inflammation: Mechanistic Aspects and Applications","volume":"9","author":"Zhao","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1001\/archneur.55.11.1449","article-title":"Folate, Vitamin B12, and Serum Total Homocysteine Levels in Confirmed Alzheimer Disease","volume":"55","author":"Clarke","year":"1998","journal-title":"Arch. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1016\/j.lfs.2005.02.014","article-title":"Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer\u2019s disease and Parkinson\u2019s disease","volume":"77","author":"Isobe","year":"2005","journal-title":"Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1056\/NEJMoa011613","article-title":"Plasma Homocysteine As a Risk Factor for Dementia and Alzheimer\u2019s Disease","volume":"346","author":"Seshadri","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/ana.20645","article-title":"Plasma total homocysteine and memory in the elderly: The Hordaland homocysteine study","volume":"58","author":"Nurk","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S1474-4422(03)00438-1","article-title":"Homocysteine and Alzheimer\u2019s disease","volume":"2","author":"Morris","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Smith, A.D., Smith, S.M., de Jager, C.A., Whitbread, P., Johnston, C., Agacinski, G., Oulhaj, A., Bradley, K.M., Jacoby, R., and Refsum, H. (2010). Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012244"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9523","DOI":"10.1073\/pnas.1301816110","article-title":"Preventing Alzheimer\u2019s disease-related gray matter atrophy by B-vitamin treatment","volume":"110","author":"Douaud","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kennedy, D. (2016). B Vitamins and the Brain: Mechanisms, Dose and Efficacy\u2014A Review. Nutrients, 8.","DOI":"10.3390\/nu8020068"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.1056\/NEJMoa054025","article-title":"A Controlled Trial of Homocysteine Lowering and Cognitive Performance","volume":"354","author":"McMahon","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1159\/000095802","article-title":"Behavioural and psychological symptoms of Alzheimer type dementia are not correlated with plasma homocysteine concentration","volume":"22","author":"Tabet","year":"2006","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.amjmed.2010.01.017","article-title":"Effect of Folic Acid, with or without Other B Vitamins, on Cognitive Decline: Meta-Analysis of Randomized Trials","volume":"123","author":"Wald","year":"2010","journal-title":"Am. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3945\/ajcn.113.076349","article-title":"Effects of homocysteine lowering with B vitamins on cognitive aging: Meta-analysis of 11 trials with cognitive data on 22,000 individuals","volume":"100","author":"Clarke","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3233\/JAD-171042","article-title":"Homocysteine and Dementia: An International Consensus Statement","volume":"62","author":"Smith","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1146\/annurev-nutr-071715-050947","article-title":"Homocysteine, B Vitamins, and Cognitive Impairment","volume":"36","author":"Smith","year":"2016","journal-title":"Annu. Rev. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1194\/jlr.R076331","article-title":"Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer\u2019s disease: A rationale for multi-nutrient dementia prevention","volume":"58","author":"Grimm","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"547","DOI":"10.3233\/JAD-150777","article-title":"Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment","volume":"50","author":"Oulhaj","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"McCleery, J., Abraham, R.P., Denton, D.A., Rutjes, A.W.S., Chong, L.-Y., Al-Assaf, A.S., Griffith, D.J., Rafeeq, S., Yaman, H., and Malik, M.A. (2018). Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment. Cochrane Database Syst. Rev., 2018.","DOI":"10.1002\/14651858.CD011905.pub2"},{"key":"ref_28","first-page":"1422","article-title":"Homocysteine and Neurologic Disease","volume":"57","year":"2000","journal-title":"Arch. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1016\/j.febslet.2006.04.088","article-title":"Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia","volume":"580","author":"Obeid","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5923","DOI":"10.1073\/pnas.94.11.5923","article-title":"Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor","volume":"94","author":"Lipton","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0006-8993(87)91531-9","article-title":"l-Homocysteate is a potent neurotoxin on cultured cortical neurons","volume":"437","author":"Kim","year":"1987","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/pr034115o","article-title":"Molecular Analysis of Homocysteic Acid-Induced Neuronal Stress","volume":"3","author":"Sommer","year":"2004","journal-title":"J. Proteome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jns.2003.11.009","article-title":"Implications for hyperhomocysteinemia: Not homocysteine but its oxidized forms strongly inhibit neuronal network activity","volume":"218","author":"Hoinkes","year":"2004","journal-title":"J. Neurol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s10517-006-0288-8","article-title":"Effect of Homocysteine and Homocysteic Acid on Glutamate Receptors on Rat Lymphocytes","volume":"142","author":"Vladychenskaya","year":"2006","journal-title":"Bull. Exp. Biol. Med. Vol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jansen, D., Zerbi, V., Arnoldussen, I.A.C., Wiesmann, M., Rijpma, A., Fang, X.T., Dederen, P.J., Mutsaers, M.P.C., Broersen, L.M., and L\u00fctjohann, D. (2013). Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in A\u03b2PPswe-PS1dE9 Mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075393"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.jpba.2019.06.008","article-title":"A validated LC\u2013MS\/MS method for the determination of homocysteic acid in biological samples","volume":"174","author":"Gurke","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.nlm.2009.02.002","article-title":"Intrasession and intersession habituation in mice: From inbred strain variability to linkage analysis","volume":"92","author":"Bolivar","year":"2009","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00210-018-1589-y","article-title":"Assessment of spatial learning and memory in the Barnes maze task in rodents\u2014Methodological consideration","volume":"392","author":"Gawel","year":"2019","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kaidanovich-Beilin, O., Lipina, T., Vukobradovic, I., Roder, J., and Woodgett, J.R. (2011). Assessment of Social Interaction Behaviors. J. Vis. Exp., 2473.","DOI":"10.3791\/2473-v"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1601-1848.2004.00076.x","article-title":"Sociability and preference for social novelty in five inbred strains: An approach to assess autistic-like behavior in mice","volume":"3","author":"Moy","year":"2004","journal-title":"Genes Brain Behav."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14613","DOI":"10.1038\/srep14613","article-title":"Bridging the translational divide: Identical cognitive touchscreen testing in mice and humans carrying mutations in a disease-relevant homologous gene","volume":"5","author":"Nithianantharajah","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16363","DOI":"10.1038\/s41598-019-51928-w","article-title":"Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer\u2019s disease pathology","volume":"9","author":"Jacob","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bbr.2017.08.048","article-title":"Automated dissection of permanent effects of hippocampal or prefrontal lesions on performance at spatial, working memory and circadian timing tasks of C57BL\/6 mice in IntelliCage","volume":"352","author":"Voikar","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1111\/j.1601-183X.2010.00606.x","article-title":"Consistent behavioral phenotype differences between inbred mouse strains in the IntelliCage","volume":"9","author":"Krackow","year":"2010","journal-title":"Genes Brain Behav."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.bbr.2015.01.016","article-title":"Age dependent levels of plasma homocysteine and cognitive performance","volume":"283","author":"Agrawal","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.tins.2010.05.004","article-title":"\u2018Too much good news\u2019\u2014Are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer\u2019s disease?","volume":"33","author":"Zahs","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00415-007-0558-z","article-title":"Gender differences in brain reserve","volume":"254","author":"Perneczky","year":"2007","journal-title":"J. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"37","DOI":"10.2147\/CLEP.S37929","article-title":"Clinical epidemiology of Alzheimer\u2019 disease: Assessing sex and gender differences","volume":"6","author":"Mielke","year":"2014","journal-title":"Clin. Epidemiol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Sakakibara, Y., Sekiya, M., Saito, T., Saido, T.C., and Iijima, K.M. (2019). Amyloid-\u03b2 plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer\u2019s disease. BMC Neurosci., 20.","DOI":"10.1186\/s12868-019-0496-6"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.neurobiolaging.2018.10.026","article-title":"Age-dependent behavioral and biochemical characterization of single APP knock-in mouse (APPNL-G-F\/NL-G-F) model of Alzheimer\u2019s disease","volume":"75","author":"Mehla","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.bbr.2017.11.017","article-title":"Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL\u2212G\u2212F mice before prominent plaque deposition","volume":"364","author":"Shah","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.bbr.2017.09.006","article-title":"Reduction in open field activity in the absence of memory deficits in the App NL\u2212G\u2212F knock-in mouse model of Alzheimer\u2019s disease","volume":"336","author":"Whyte","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Sakakibara, Y., Sekiya, M., Saito, T., Saido, T.C., and Iijima, K.M. (2018). Cognitive and emotional alterations in App knock-in mouse models of A\u03b2 amyloidosis. BMC Neurosci., 19.","DOI":"10.1186\/s12868-018-0446-8"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.nlm.2016.07.001","article-title":"Cognitive deficits in single App knock-in mouse models","volume":"135","author":"Masuda","year":"2016","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13024-017-0231-7","article-title":"Practical considerations for choosing a mouse model of Alzheimer\u2019s disease","volume":"12","author":"Jankowsky","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/jcbfm.2013.1","article-title":"Induction of Hyperhomocysteinemia Models Vascular Dementia by Induction of Cerebral Microhemorrhages and Neuroinflammation","volume":"33","author":"Sudduth","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"M348","DOI":"10.1093\/gerona\/54.7.M348","article-title":"Anxiety in Alzheimer\u2019s Disease: Prevalence and Comorbidity","volume":"54","author":"Teri","year":"1999","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.mcn.2007.12.018","article-title":"B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-\u03b2 deposition in mice","volume":"37","author":"Fuso","year":"2008","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.2353\/ajpath.2009.081036","article-title":"Hyperhomocysteinemia Increases \u03b2-Amyloid by Enhancing Expression of \u03b3-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain","volume":"174","author":"Zhang","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1523\/JNEUROSCI.22-05-01752.2002","article-title":"Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer\u2019s disease","volume":"22","author":"Kruman","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.neurobiolaging.2006.05.035","article-title":"Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet","volume":"28","author":"Bernardo","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"12474","DOI":"10.1073\/pnas.0805350105","article-title":"B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice","volume":"105","author":"Troen","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.euroneuro.2019.10.007","article-title":"Be positive about negatives\u2013recommendations for the publication of negative (or null) results","volume":"29","author":"Bespalov","year":"2019","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1373\/clinchem.2003.021634","article-title":"Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion","volume":"50","author":"Refsum","year":"2004","journal-title":"Clin. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neulet.2010.07.075","article-title":"Aging and antioxidants modulate rat brain levels of homocysteine and dehydroepiandrosterone sulphate (DHEA-S): Implications in the pathogenesis of Alzheimer\u2019s disease","volume":"483","author":"Sinha","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1007\/s11745-001-0679-7","article-title":"The Hordaland Homocysteine Studies","volume":"36","author":"Ueland","year":"2001","journal-title":"Lipids"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1152\/physiolgenomics.00199.2004","article-title":"Homocysteine levels in A\/J and C57BL\/6J mice: Genetic, diet, gender, and parental effects","volume":"21","author":"Ernest","year":"2005","journal-title":"Physiol. Genom."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3233\/JAD-2010-100171","article-title":"Severe In Vivo Hyper-Homocysteinemia is not Associated with Elevation of Amyloid-\u03b2 Peptides in the Tg2576 Mice","volume":"21","author":"Zhuo","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Mikoda, N., Kitazawa, M., and LaFerla, F.M. (2010). Treatment of Alzheimer\u2019s Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008593"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jnutbio.2014.08.002","article-title":"Impact of dietary n-3 polyunsaturated fatty acids on cognition, motor skills and hippocampal neurogenesis in developing C57BL\/6J mice","volume":"26","author":"Janssen","year":"2015","journal-title":"J. Nutr. Biochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/6846721","article-title":"A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice","volume":"2016","author":"Wiesmann","year":"2016","journal-title":"Neural Plast."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.neuroscience.2007.08.018","article-title":"A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer\u2019s transgenic mice","volume":"149","author":"Arendash","year":"2007","journal-title":"Neuroscience"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/alzrt224","article-title":"The S-Connect study: Results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer\u2019s disease","volume":"5","author":"Shah","year":"2013","journal-title":"Alzheimers Res. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.trci.2019.08.002","article-title":"Exploring effects of Souvenaid on cerebral glucose metabolism in Alzheimer\u2019s disease","volume":"5","author":"Scheltens","year":"2019","journal-title":"Alzheimers Dement. Transl. Res. Clin. Interv."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","article-title":"A critical appraisal of amyloid-\u03b2-targeting therapies for Alzheimer disease","volume":"15","author":"Panza","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1001\/archneur.65.11.1509","article-title":"Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly","volume":"65","author":"Aizenstein","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1703531","DOI":"10.1080\/19420862.2019.1703531","article-title":"Antibodies to watch in 2020","volume":"12","author":"Kaplon","year":"2020","journal-title":"MAbs"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnbeh.2017.00013","article-title":"Behavior of Male and Female C57BL\/6J Mice Is More Consistent with Repeated Trials in the Elevated Zero Maze than in the Elevated Plus Maze","volume":"11","author":"Tucker","year":"2017","journal-title":"Front. Behav. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1101\/lm.334306","article-title":"Spatial and nonspatial escape strategies in the Barnes maze","volume":"13","author":"Harrison","year":"2006","journal-title":"Learn. Mem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00213-009-1526-3","article-title":"A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: A translational rodent model of cognitive impairments in neurodegenerative disease","volume":"205","author":"Talpos","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_81","unstructured":"Paxinos, G., and Franklin, K.B.J. (2013). The Mouse Brain in Stereotaxic Coordinates, Academic Press. [4th ed.]."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.cobeha.2018.06.016","article-title":"Inclusion of females does not increase variability in rodent research studies","volume":"23","author":"Beery","year":"2018","journal-title":"Curr. Opin. Behav. Sci."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/11\/3248\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:26:53Z","timestamp":1760178413000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/11\/3248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,23]]},"references-count":82,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["nu12113248"],"URL":"https:\/\/doi.org\/10.3390\/nu12113248","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2020,10,23]]}}}