{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T13:31:48Z","timestamp":1775827908571,"version":"3.50.1"},"reference-count":75,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"VEGA","award":["1\/0192\/22"],"award-info":[{"award-number":["1\/0192\/22"]}]},{"name":"VEGA","award":["1\/0274\/23"],"award-info":[{"award-number":["1\/0274\/23"]}]},{"name":"Ministry of Education of the Slovak Republic","award":["1\/0192\/22"],"award-info":[{"award-number":["1\/0192\/22"]}]},{"name":"Ministry of Education of the Slovak Republic","award":["1\/0274\/23"],"award-info":[{"award-number":["1\/0274\/23"]}]},{"name":"EU sources","award":["1\/0192\/22"],"award-info":[{"award-number":["1\/0192\/22"]}]},{"name":"EU sources","award":["1\/0274\/23"],"award-info":[{"award-number":["1\/0274\/23"]}]},{"name":"European Regional Development Fund","award":["1\/0192\/22"],"award-info":[{"award-number":["1\/0192\/22"]}]},{"name":"European Regional Development Fund","award":["1\/0274\/23"],"award-info":[{"award-number":["1\/0274\/23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Multifactorial interactions, including nutritional state, likely participate in neurodegeneration\u2019s pathogenesis and evolution. Dysregulation in methionine (Met) metabolism could lead to the development of hyperhomocysteinaemia (hHcy), playing an important role in neuronal dysfunction, which could potentially lead to the development of Alzheimer\u2019s disease (AD)-like pathological features. This study combines proton magnetic resonance spectroscopy (1H MRS) with immunohistochemical analysis to examine changes in the metabolic ratio and histomorphological alterations in the dorsal rat hippocampus (dentate gyrus\u2014DG) subjected to a high Met diet. Male Wistar rats (420\u2013480 g) underwent hHcy evoked by a Met-enriched diet (2 g\/kg of weight\/day) lasting four weeks. Changes in the metabolic ratio profile and significant histomorphological alterations have been found in the DG of hHcy rats. We have detected increased morphologically changed neurons and glial cells with increased neurogenic markers and apolipoprotein E positivity parallel with a diminished immunosignal for the N-Methyl-D-Aspartate receptor 1 in hHcy animals. A Met diet induced hHcy, likely via direct Hcy neurotoxicity, an interference with one carbon unit metabolism, and\/or epigenetic regulation. These conditions lead to the progression of neurodegeneration and the promotion of AD-like pathological features in the less vulnerable hippocampal DG, which presents a plausible therapeutic target.<\/jats:p>","DOI":"10.3390\/cells12162087","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T10:42:29Z","timestamp":1692268949000},"page":"2087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alzheimer\u2019s Disease-like Pathological Features in the Dorsal Hippocampus of Wild-Type Rats Subjected to Methionine-Diet-Evoked Mild Hyperhomocysteinaemia"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6802-5309","authenticated-orcid":false,"given":"Maria","family":"Kovalska","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1529-1675","authenticated-orcid":false,"given":"Petra","family":"Hnilicova","sequence":"additional","affiliation":[{"name":"Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"Kalenska","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Adamkov","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Libusa","family":"Kovalska","sequence":"additional","affiliation":[{"name":"Clinic of Stomatology and Maxillofacial Surgery, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Lehotsky","sequence":"additional","affiliation":[{"name":"Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"},{"name":"Department of Medical Biochemistry, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"ref_1","first-page":"1299","article-title":"Meta-analysis of modifiable risk factors for Alzheimer\u2019s disease","volume":"86","author":"Xu","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_2","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. Alzheimer\u2019s Dis."},{"key":"ref_3","unstructured":"Pluta, R. (2019). Brain Ischemia: Alzheimer\u2019s Disease Mechanisms, Nova Science Pub. Inc.. [1st ed.]."},{"key":"ref_4","first-page":"648","article-title":"Ischemic Brain Injury in Hyperhomocysteinemia","volume":"16","author":"Lehotsky","year":"2021","journal-title":"Cereb. Ischemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"617071","DOI":"10.3389\/fnagi.2020.617071","article-title":"Does Diet Have a Role in the Treatment of Alzheimer\u2019s Disease?","volume":"12","author":"Thelen","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6683318","DOI":"10.1155\/2021\/6683318","article-title":"High Methionine Diet-Induced Alzheimer\u2019s Disease like Symptoms Are Accompanied by 5-Methylcytosine Elevated Levels in the Brain","volume":"2021","author":"Pi","year":"2021","journal-title":"Behav. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"363985","DOI":"10.1155\/2014\/363985","article-title":"Huperzine A in the Treatment of Alzheimer\u2019s Disease and Vascular Dementia: A Meta-Analysis","volume":"2014","author":"Xing","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.fertnstert.2013.01.124","article-title":"Epigenetic disorders and male subfertility","volume":"99","author":"Boissonnas","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"112045","DOI":"10.1016\/j.exger.2022.112045","article-title":"Homocysteine\u2014A predictor for five year-mortality in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer\u2019s dementia","volume":"172","author":"Futschek","year":"2023","journal-title":"Exp. Gerontol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1039\/C9FO02819F","article-title":"Dietary methionine restriction improves the impairment of cardiac function in middle-aged obese mice","volume":"11","author":"Han","year":"2020","journal-title":"Food Funct."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Esse, R., Barroso, M., De Almeida, I.T., and Castro, R. (2019). The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040867"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1016\/j.jhep.2022.06.033","article-title":"Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation","volume":"77","author":"Tripathi","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1007\/s11011-018-0298-z","article-title":"High methionine, low folate and low vitamin B6\/B12 (HM-LF-LV) diet causes neurodegeneration and subsequent short-term memory loss","volume":"33","author":"Nuru","year":"2018","journal-title":"Metab. Brain Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12974-019-1685-z","article-title":"Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events","volume":"16","author":"Weekman","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.neuroscience.2016.11.024","article-title":"Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID)","volume":"341","author":"Sudduth","year":"2017","journal-title":"Neuroscience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1080\/02699052.2020.1725835","article-title":"Traumatic microbleeds persist for up to five years following traumatic brain injury despite resolution of other acute findings on MRI","volume":"34","author":"Rizk","year":"2020","journal-title":"Brain Inj."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.neulet.2011.02.076","article-title":"Methionine diet-induced hyperhomocysteinemia accelerates cerebral aneurysm formation in rats","volume":"494","author":"Xu","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1007\/s11064-021-03485-w","article-title":"Hyperhomocysteinemia Induces Rat Memory Impairment Via Injuring Hippocampal CA3 Neurons and Downregulating cAMP Response Element-Binding Protein (CREB) Phosphorylation","volume":"47","author":"Liu","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"577843","DOI":"10.1016\/j.jneuroim.2022.577843","article-title":"L-methionine enhances neuroinflammation and impairs neurogenesis: Implication for Alzheimer\u2019s disease","volume":"366","author":"Alachkar","year":"2022","journal-title":"J. Neuroimmunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1007\/s12035-019-01799-z","article-title":"Expression of the Tau Protein and Amyloid Protein Precursor Processing Genes in the CA3 Area of the Hippocampus in the Ischemic Model of Alzheimer\u2019s Disease in the Rat","volume":"57","author":"Pluta","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fnmol.2015.00087","article-title":"Age-Dependent Degeneration of Mature Dentate Gyrus Granule Cells Following NMDA Receptor Ablation","volume":"8","author":"Watanabe","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kovalska, M., Hnilicova, P., Kalenska, D., Tothova, B., Adamkov, M., and Lehotsky, J. (2019). Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246234"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kovalska, M., Baranovicova, E., Kalenska, D., Tomascova, A., Adamkov, M., Kovalska, L., and Lehotsky, J. (2021). Methionine Diet Evoked Hyperhomocysteinemia Causes Hippocampal Alterations, Metabolomics Plasma Changes and Behavioral Pattern in Wild Type Rats. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094961"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kovalska, M., Hnilicova, P., Kalenska, D., Tomascova, A., Adamkov, M., and Lehotsky, J. (2020). Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia. Biomolecules, 10.","DOI":"10.3390\/biom10081128"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40478-022-01485-7","article-title":"Differential vulnerability of the dentate gyrus to tauopathies in dementias","volume":"11","author":"Kawles","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1038\/s41593-020-00728-x","article-title":"Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer\u2019s disease","volume":"23","author":"Richetin","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_27","unstructured":"Lowes, Z. (2015). Dentate Gyrus: Structure, Role in Disease, and Potential Health Implications, Nova Science. [1st ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1142\/S0219635216500175","article-title":"Impaired neurogenesis of the dentate gyrus is associated with pattern separation deficits: A computational study","volume":"15","author":"Faghihi","year":"2016","journal-title":"J. Integr. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11795735231160025","DOI":"10.1177\/11795735231160025","article-title":"Hippocampal vulnerability to hyperhomocysteinemia worsens pathological outcomes of mild traumatic brain injury in rats","volume":"15","author":"Tchantchou","year":"2023","journal-title":"J. Central Nerv. Syst. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1007\/s11357-021-00354-w","article-title":"In vivo proton magnetic resonance spectroscopy detection of metabolite abnormalities in aged Tat-transgenic mouse brain","volume":"43","author":"Paris","year":"2021","journal-title":"Geroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"306","DOI":"10.3389\/fnins.2017.00306","article-title":"Influence of Estrogen Modulation on Glia Activation in a Murine Model of Parkinson\u2019s Disease","volume":"11","author":"Siani","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.brainres.2018.12.030","article-title":"Contributions of sex to cerebrovascular function and pathology","volume":"1710","author":"Robison","year":"2018","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"953417","DOI":"10.3389\/fnins.2022.953417","article-title":"The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia","volume":"16","author":"Zhu","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19129","DOI":"10.1038\/s41598-022-23801-w","article-title":"Females exhibit higher GluA2 levels and outperform males in active place avoidance despite increased amyloid plaques in TgF344-Alzheimer\u2019s rats","volume":"12","author":"Chaudry","year":"2022","journal-title":"Sci Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1042\/cs1000127","article-title":"Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation","volume":"100","author":"Labinjoh","year":"2001","journal-title":"Clin. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.atherosclerosis.2003.08.003","article-title":"Arterial stiffness is rapidly induced by raising the plasma homocysteine concentration with methionine","volume":"171","author":"Nestel","year":"2003","journal-title":"Atherosclerosis"},{"key":"ref_37","unstructured":"Paxinos, G., and Watson, C. (2006). The Rat Brain in Stereotaxic Coordinates, Academic Press. [6th ed.]."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14668","DOI":"10.1038\/s41598-018-32859-4","article-title":"A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein","volume":"8","author":"Dusart","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_39","first-page":"31","article-title":"Association of induced hyperhomocysteinemia with neurodegeneration in rat entorhinal cortex-hippocampal system after global brain ischemia: A progression of Alzheimer\u2019s disease-like pathological features","volume":"61","author":"Kovalska","year":"2019","journal-title":"Act. Nerv. Super. Rediviva"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/jnc.14011","article-title":"Microtubule dynamics and the neurodegenerative triad of Alzheimer\u2019s disease: The hidden connection","volume":"143","author":"Brandt","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1001\/jamapsychiatry.2019.1694","article-title":"Association of Methionine to Homocysteine Status with Brain Magnetic Resonance Imaging Measures and Risk of Dementia","volume":"76","author":"Hooshmand","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/S0741-5214(03)00923-6","article-title":"The prevalence of hyperhomocysteinemia, methylene tetrahydrofolate reductase C677T mutation, and vitamin B12 and folate deficiency in patients with chronic venous insufficiency","volume":"38","author":"Sam","year":"2003","journal-title":"J. Vasc. Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"19880","DOI":"10.1038\/srep19880","article-title":"Magnetic Resonance Spectroscopy discriminates the response to microglial stimulation of wild type and Alzheimer\u2019s disease models","volume":"6","author":"Pardon","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1729071","DOI":"10.1155\/2018\/1729071","article-title":"Quantitative Radiomics: Impact of Pulse Sequence Parameter Selection on MRI-Based Textural Features of the Brain","volume":"2018","author":"Ford","year":"2018","journal-title":"Contrast Media Mol. Imaging"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"807","DOI":"10.3389\/fneur.2019.00807","article-title":"Deciphering the Link Between Hyperhomocysteinemia and Ceramide Metabolism in Alzheimer-Type Neurodegeneration","volume":"10","author":"Kassis","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1007\/s11481-013-9460-x","article-title":"Magnetic Resonance Spectroscopy to Assess NeuroInflammation and Neuropathic Pain","volume":"8","author":"Chang","year":"2013","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fnagi.2015.00202","article-title":"Probing astrocyte metabolism in vivo: Proton magnetic resonance spectroscopy in the injured and aging brain","volume":"7","author":"Harris","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1111\/j.1528-1167.2012.03685.x","article-title":"In vivo imaging of glia activation using1H-magnetic resonance spectroscopy to detect putative biomarkers of tissue epileptogenicity","volume":"53","author":"Filibian","year":"2012","journal-title":"Epilepsia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1152\/physrev.00003.2018","article-title":"Homocysteine Modification in Protein Structure\/Function and Human Disease","volume":"99","author":"Jakubowski","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1016\/j.neurobiolaging.2014.03.026","article-title":"Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer\u2019s disease","volume":"35","author":"Hanzel","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4145708","DOI":"10.1155\/2016\/4145708","article-title":"Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons","volume":"2016","author":"Seifert","year":"2016","journal-title":"Neural Plast."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.neuron.2008.11.013","article-title":"Dynamic Microtubules Regulate Dendritic Spine Morphology and Synaptic Plasticity","volume":"61","author":"Jaworski","year":"2009","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1172\/JCI64575","article-title":"Cerebrospinal fluid\u2013based kinetic biomarkers of axonal transport in monitoring neurodegeneration","volume":"122","author":"Fanara","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1096\/fj.08-105866","article-title":"IFN-\u03b3 enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer\u2019s disease","volume":"22","author":"Baron","year":"2008","journal-title":"FASEB J."},{"key":"ref_55","first-page":"39","article-title":"Neurogenesis Unchanged by MTHFR Deficiency in Three-Week-Old Mice","volume":"31","author":"Owens","year":"2016","journal-title":"J. Young Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/neup.12445","article-title":"Enhanced neurogenesis and possible synaptic reorganization in the piriform cortex of adult rat following kainic acid-induced status epilepticus","volume":"38","author":"Sakurai","year":"2017","journal-title":"Neuropathology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1326-4-21","article-title":"ApoE isoform-dependent changes in hippocampal synaptic function","volume":"4","author":"Korwek","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13195-017-0270-x","article-title":"One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: Homocysteine and beyond","volume":"9","author":"Dayon","year":"2017","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"178","DOI":"10.4331\/wjbc.v7.i1.178","article-title":"High levels of homocysteine downregulate apolipoprotein E expressionvianuclear factor kappa B","volume":"7","author":"Trusca","year":"2016","journal-title":"World J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nature24016","article-title":"ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy","volume":"549","author":"Shi","year":"2017","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.neuron.2018.05.008","article-title":"APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer\u2019s Disease Phenotypes in Human iPSC-Derived Brain Cell Types","volume":"98","author":"Lin","year":"2018","journal-title":"Neuron"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1111\/j.1471-4159.2009.06207.x","article-title":"Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death","volume":"110","author":"Poddar","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Moretti, R., and Caruso, P. (2019). The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010231"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/jnc.13741","article-title":"Glycine release from astrocytes via functional reversal of GlyT1","volume":"140","author":"Shibasaki","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1742-2094-1-12","article-title":"Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors","volume":"1","author":"Rosi","year":"2004","journal-title":"J. Neuroinflamm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0304-3940(94)90233-X","article-title":"NMDA receptor (NMDAR1) expression in the rat hippocampus after forebrain ischemia","volume":"170","author":"Sugimoto","year":"1994","journal-title":"Neurosci. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1080\/1028415X.2022.2060642","article-title":"Homocysteine can aggravate depressive like behaviors in a middle cerebral artery occlusion\/reperfusion rat model: A possible role for NMDARs-mediated synaptic alterations","volume":"26","author":"Wang","year":"2022","journal-title":"Nutr. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"8686","DOI":"10.1523\/JNEUROSCI.0435-21.2021","article-title":"APOE4 Affects Basal and NMDAR-Mediated Protein Synthesis in Neurons by Perturbing Calcium Homeostasis","volume":"41","author":"Ramakrishna","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1007\/s10571-017-0473-5","article-title":"Effect of Hyperhomocysteinemia on Redox Balance and Redox Defence Enzymes in Ischemia\u2013Reperfusion Injury and\/or After Ischemic Preconditioning in Rats","volume":"37","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.arr.2018.10.010","article-title":"Homocysteine and age-associated disorders","volume":"49","author":"Ostrakhovitch","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.archger.2004.04.045","article-title":"HOMOCYSTEINE AND COGNITIVE PERFORMANCE IN HEALTHY ELDERLY SUBJECTS","volume":"38","author":"Ravaglia","year":"2004","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1212\/01.wnl.0000183063.99107.5c","article-title":"Association of homocysteine with plasma amyloid \u03b2 protein in aging and neurodegenerative disease","volume":"65","author":"Irizarry","year":"2005","journal-title":"Neurology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"790","DOI":"10.3945\/ajcn.116.137927","article-title":"Vitamin B-12 status and neurologic function in older people: A cross-sectional analysis of baseline trial data from the Older People and Enhanced Neurological Function (OPEN) study","volume":"104","author":"Miles","year":"2016","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neulet.2015.06.009","article-title":"Methylation analysis of multiple genes in blood DNA of Alzheimer\u2019s disease and healthy individuals","volume":"600","author":"Tannorella","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1089\/ars.2021.0269","article-title":"Does Risk of Hyperhomocysteinemia Depend on Thiol-Disulfide Exchange Reactions of Albumin and Homocysteine?","volume":"38","author":"Coppo","year":"2023","journal-title":"Antioxid. 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