{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T18:08:26Z","timestamp":1779386906502,"version":"3.53.1"},"reference-count":80,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cMinistero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca\u201d","award":["2022ZTKFXS"],"award-info":[{"award-number":["2022ZTKFXS"]}]},{"name":"\u201cRicerca Scientifica di Ateneo\u201d","award":["2023\u20132025"],"award-info":[{"award-number":["2023\u20132025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mitochondrial dysfunction is a relevant hallmark of Alzheimer\u2019s disease (AD), contributing to the impaired metabolic homeostasis involved in neuronal loss and cognitive decline. In this study, we target the metabolic dysfunction occurring in AD through a novel pharmacological approach involving the modulation of glutamate dehydrogenase (GDH), which converts glutamate to \u03b1-ketoglutarate and supports the tricarboxylic acid (TCA) cycle. In our experimental models (i.e., differentiated SH-SY5Y cells and primary rat cortical neurons exposed to glyceraldehyde and amyloid-beta peptide 1-42, respectively), the allosteric GDH activator 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) increased mitochondrial ATP production, improved cellular bioenergetics, and reduced oxidative stress, ultimately promoting neuronal survival. Ionic dysfunctions in AD are linked to disrupted calcium homeostasis and organelle storing properties. In this context, GDH activation potentiated mitochondrial and endoplasmic reticulum calcium buffering capacity by enhancing store-operated calcium entry. Oxidative stress, largely driven by mitochondrial ROS overproduction, represents another major contributor to AD pathology. In our AD models BCH-mediated GDH activation reduced ROS formation and restored mitochondrial membrane potential (\u0394\u03a8m). Importantly, these metabolic and ionic improvements were associated with decreased accumulation of amyloid-\u03b2 (A\u03b21-42) and phosphorylated tau (pTau), two key AD biomarkers. Overall, modulation of the GDH\/TCA pathway represents a promising approach for restoring metabolic dysfunctions and counteracting oxidative stress and ionic dysregulation and therefore AD neurodegeneration.<\/jats:p>","DOI":"10.3390\/biom16050667","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:15:27Z","timestamp":1777630527000},"page":"667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric Activation of GDH\/TCA Pathway Reduces Pathological Build-Up and Promotes Neuronal Survival in an In Vitro Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5516-1023","authenticated-orcid":false,"given":"Tiziano","family":"Serfilippi","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7608-5589","authenticated-orcid":false,"given":"Silvia","family":"Piccirillo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Preziuso","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1392-1023","authenticated-orcid":false,"given":"Valentina","family":"Terenzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Ciancio","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Magi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-1495","authenticated-orcid":false,"given":"Vincenzo","family":"Lariccia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-4098","authenticated-orcid":false,"given":"Agnese","family":"Secondo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health, School of Medicine, University \u201cPolitecnica delle Marche\u201d, Via Tronto 10\/A, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_2","unstructured":"Clare, L., and Jeon, Y.H. (2025). World Alzheimer Report 2025: Reimagining Life with Dementia\u2014The Power of Rehabilitation, Alzheimer\u2019s Disease International."},{"key":"ref_3","unstructured":"(2022). GBD 2019 Dementia Forecasting Collaborators Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health, 7, e105\u2013e125."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"313","DOI":"10.14283\/jpad.2021.15","article-title":"The Epidemiology of Alzheimer\u2019s Disease Modifiable Risk Factors and Prevention","volume":"8","author":"Zhang","year":"2021","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ezkurdia, A., Ram\u00edrez, M.J., and Solas, M. (2023). Metabolic Syndrome as a Risk Factor for Alzheimer\u2019s Disease: A Focus on Insulin Resistance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054354"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Flores-Cordero, J.A., P\u00e9rez-P\u00e9rez, A., Jim\u00e9nez-Cortegana, C., Alba, G., Flores-Barrag\u00e1n, A., and S\u00e1nchez-Margalet, V. (2022). Obesity as a Risk Factor for Dementia and Alzheimer\u2019s Disease: The Role of Leptin. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095202"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102402","DOI":"10.1016\/j.arr.2024.102402","article-title":"Obesity-induced chronic low-grade inflammation in adipose tissue: A pathway to Alzheimer\u2019s disease","volume":"99","author":"Zhai","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bcp.2012.12.007","article-title":"Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer\u2019s disease","volume":"86","author":"Popp","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Du, Y., Yu, Z., Li, C., Zhang, Y., and Xu, B. (2025). The role of statins in dementia or Alzheimer\u2019s disease incidence: A systematic review and meta-analysis of cohort studies. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1473796"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1093\/eurjpc\/zwab208","article-title":"Statin use and risk of dementia or Alzheimer\u2019s disease: A systematic review and meta-analysis of observational studies","volume":"29","author":"Olmastroni","year":"2022","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13195-023-01360-0","article-title":"Statins and cognitive decline in patients with Alzheimer\u2019s and mixed dementia: A longitudinal registry-based cohort study","volume":"15","author":"Petek","year":"2023","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Neth, B.J., and Craft, S. (2017). Insulin Resistance and Alzheimer\u2019s Disease: Bioenergetic Linkages. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00345"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yanai, H., Adachi, H., Hakoshima, M., and Katsuyama, H. (2024). Pathology and Treatments of Alzheimer\u2019s Disease Based on Considering Changes in Brain Energy Metabolism Due to Type 2 Diabetes. Molecules, 29.","DOI":"10.20944\/preprints202410.1756.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2016.04.200","article-title":"Energy Metabolism and Inflammation in Brain Aging and Alzheimer\u2019s Disease","volume":"100","author":"Yin","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism, and Alzheimer disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e70084","DOI":"10.1111\/jnc.70084","article-title":"Neural Metabolic Networks: Key Elements of Healthy Brain Function","volume":"169","author":"Madrer","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s10545-018-0201-4","article-title":"Metabolism of amino acid neurotransmitters: The synaptic disorder underlying inherited metabolic diseases","volume":"41","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Shichkova, P., Coggan, J.S., Markram, H., Keller, D., Shichkova, P., Coggan, J.S., Markram, H., and Keller, D. (2024). Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes. Cells, 13.","DOI":"10.3389\/frym.2025.1535493"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.freeradbiomed.2022.09.032","article-title":"Altered glucose metabolism in Alzheimer\u2019s disease: Role of mitochondrial dysfunction and oxidative stress","volume":"193","author":"Dewanjee","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yao, P.J., Eren, E., Goetzl, E.J., and Kapogiannis, D. (2021). Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer\u2019s Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111587"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101619","DOI":"10.1016\/j.arr.2022.101619","article-title":"Oxidative stress: The core pathogenesis and mechanism of Alzheimer\u2019s disease","volume":"77","author":"Bai","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10573","DOI":"10.1073\/pnas.90.22.10573","article-title":"Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes","volume":"90","author":"Arispe","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6701324","DOI":"10.1155\/2016\/6701324","article-title":"Intracellular Calcium Dysregulation: Implications for Alzheimer\u2019s Disease","volume":"2016","author":"Magi","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/cbdd.14175","article-title":"Role of calcium dysregulation in Alzheimer\u2019s disease and its therapeutic implications","volume":"101","author":"Joshi","year":"2023","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Calvo-Rodriguez, M., Kharitonova, E.K., and Bacskai, B.J. (2020). Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer\u2019s Disease. Cells, 9.","DOI":"10.3390\/cells9112513"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Popugaeva, E., and Bezprozvanny, I. (2013). Role of endoplasmic reticulum Ca2+ signaling in the pathogenesis of Alzheimer disease. Front. Mol. Neurosci., 6.","DOI":"10.3389\/fnmol.2013.00029"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e21277","DOI":"10.1096\/fj.202001886R","article-title":"Lysosomal calcium is modulated by STIM1\/TRPML1 interaction which participates to neuronal survival during ischemic preconditioning","volume":"35","author":"Tedeschi","year":"2021","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2174\/1570159X22666240517101846","article-title":"Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation","volume":"23","author":"Tedeschi","year":"2025","journal-title":"Curr. Neuropharmacol."},{"key":"ref_29","first-page":"1259","article-title":"Emerging role of lysosomal calcium store as a hub of neuroprotection","volume":"17","author":"Tedeschi","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.1111\/febs.70053","article-title":"A non-redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: A new avenue for glutamate metabolism and protection in Parkinson\u2019s disease","volume":"292","author":"Preziuso","year":"2025","journal-title":"FEBS J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1471-4159.2006.03913.x","article-title":"The glutamate\/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer","volume":"98","author":"Bak","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/jnr.10041","article-title":"Kinetics and localization of brain phosphate activated glutaminase","volume":"66","author":"Kvamme","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Plaitakis, A., Kalef-Ezra, E., Kotzamani, D., Zaganas, I., and Spanaki, C. (2017). The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease. Biology, 6.","DOI":"10.3390\/biology6010011"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s11064-017-2428-0","article-title":"Glutamate Dehydrogenase, a Complex Enzyme at a Crucial Metabolic Branch Point","volume":"44","author":"Smith","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.neuint.2011.03.015","article-title":"The Human GLUD2 Glutamate Dehydrogenase and Its Regulation in Health and Disease","volume":"59","author":"Plaitakis","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3233\/JAD-215699","article-title":"Alzheimer\u2019s Disease: Key Insights from Two Decades of Clinical Trial Failures","volume":"87","author":"Kim","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yiannopoulou, K.G., Anastasiou, A.I., Zachariou, V., and Pelidou, S.-H. (2019). Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines, 7.","DOI":"10.20944\/preprints201909.0270.v1"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Papaliagkas, V. (2025). Anti-Amyloid Therapies for Alzheimer\u2019s Disease: Progress, Pitfalls, and the Path Ahead. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199529"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"37468","DOI":"10.1038\/srep37468","article-title":"Glutamate dehydrogenase activator BCH stimulating reductive amination prevents high fat\/high fructose diet-induced steatohepatitis and hyperglycemia in C57BL\/6J mice","volume":"5","author":"Han","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5460","DOI":"10.1073\/pnas.78.9.5460","article-title":"Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid","volume":"78","author":"Sener","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1046\/j.1471-4159.2000.0751862.x","article-title":"Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human glutamate dehydrogenases are regulated by distinct allosteric mechanisms: Implications for biologic function","volume":"75","author":"Plaitakis","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1046\/j.1471-4159.1997.68051804.x","article-title":"Nerve Tissue-Specific Human Glutamate Dehydrogenase That Is Thermolabile and Highly Regulated by ADP","volume":"68","author":"Shashidharan","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neuint.2009.03.001","article-title":"The human GLUD2 glutamate dehydrogenase: Localization and functional aspects","volume":"55","author":"Zaganas","year":"2009","journal-title":"Neurochem. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/jnr.21197","article-title":"Properties and Molecular Evolution of Human GLUD2 (Neural and Testicular Tissue-Specific) Glutamate Dehydrogenase","volume":"85","author":"Kanavouras","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"31380","DOI":"10.1074\/jbc.M110.146084","article-title":"Estrogen Modification of Human Glutamate Dehydrogenases Is Linked to Enzyme Activation State","volume":"285","author":"Borompokas","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1007\/s11064-013-1235-5","article-title":"Heterogeneous Cellular Distribution of Glutamate Dehydrogenase in Brain and in Non-Neural Tissues","volume":"39","author":"Spanaki","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6568","DOI":"10.1021\/acs.biochem.6b00979","article-title":"Identification of a Novel Activator of Mammalian Glutamate Dehydrogenase","volume":"55","author":"Smith","year":"2016","journal-title":"Biochemistry"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Filograna, R., Civiero, L., Ferrari, V., Codolo, G., Greggio, E., Bubacco, L., Beltramini, M., and Bisaglia, M. (2015). Analysis of the Catecholaminergic Phenotype in Human SH-SY5Y and BE(2)-M17 Neuroblastoma Cell Lines upon Differentiation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136769"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"102268","DOI":"10.1016\/j.ceca.2020.102268","article-title":"NCX1 and EAAC1 transporters are involved in the protective action of glutamate in an in vitro Alzheimer\u2019s disease-like model","volume":"91","author":"Magi","year":"2020","journal-title":"Cell Calcium"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/cdd.2014.32","article-title":"Endoplasmic reticulum refilling and mitochondrial calcium extrusion promoted in neurons by NCX1 and NCX3 in ischemic preconditioning are determinant for neuroprotection","volume":"21","author":"Sisalli","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"106020","DOI":"10.1016\/j.nbd.2023.106020","article-title":"Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation","volume":"178","author":"Tedeschi","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"13313","DOI":"10.1038\/srep13313","article-title":"Glyceraldehyde caused Alzheimer\u2019s disease-like alterations in diagnostic marker levels in SH-SY5Y human neuroblastoma cells","volume":"5","author":"Koriyama","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Uras, G., Li, X., Manca, A., Pantaleo, A., Bo, M., Xu, J., Allen, S., and Zhu, Z. (2022). Development of p-Tau Differentiated Cell Model of Alzheimer\u2019s Disease to Screen Novel Acetylcholinesterase Inhibitors. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314794"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Twarda-Clapa, A., Olczak, A., Bia\u0142kowska, A.M., and Kozio\u0142kiewicz, M. (2022). Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells, 11.","DOI":"10.3390\/cells11081312"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Tatton, W.G., Chalmers-Redman, R.M., Elstner, M., Leesch, W., Jagodzinski, F.B., Stupak, D.P., Sugrue, M.M., and Tatton, N.A. (2000). Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. Advances in Research on Neurodegeneration, Springer.","DOI":"10.1007\/978-3-7091-6301-6_5"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1042\/bj0490113","article-title":"On the mechanism of the inhibition of glycolysis by glyceraldehyde","volume":"49","author":"Needham","year":"1951","journal-title":"Biochem. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"115869","DOI":"10.1016\/j.bcp.2023.115869","article-title":"A strategic tool to improve the study of molecular determinants of Alzheimer\u2019s disease: The role of glyceraldehyde","volume":"218","author":"Piccirillo","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2.26.1","DOI":"10.1002\/cptx.21","article-title":"Quantification of lactate dehydrogenase for cell viability testing using cell lines and primary cultured astrocytes","volume":"72","author":"Kaja","year":"2017","journal-title":"Curr. Protoc. Toxicol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S1387-2656(05)11004-7","article-title":"Tetrazolium dyes as tools in cell biology: New insights into their cellular reduction","volume":"11","author":"Berridge","year":"2005","journal-title":"Biotechnol. Annu. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"pdb-prot095505","DOI":"10.1101\/pdb.prot095505","article-title":"Analysis of Cell Viability by the MTT Assay","volume":"2018","author":"Kumar","year":"2018","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"927","DOI":"10.3233\/JAD-132084","article-title":"Rice bran extract compensates mitochondrial dysfunction in a cellular model of early Alzheimer\u2019s disease","volume":"43","author":"Hagl","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Magi, S., Lariccia, V., Castaldo, P., Arcangeli, S., Nasti, A.A., Giordano, A., and Amoroso, S. (2012). Physical and Functional Interaction of NCX1 and EAAC1 Transporters Leading to Glutamate-Enhanced ATP Production in Brain Mitochondria. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034015"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s11064-025-04353-7","article-title":"ALDH2 Overexpression Improves the Blood-brain Barrier and Represses Mitochondrial Dysfunction in Chronic Cerebral Hypoperfusion Through the SIRT1\/ROS Axis","volume":"50","author":"Liu","year":"2025","journal-title":"Neurochem. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"pdb-prot087361","DOI":"10.1101\/pdb.prot087361","article-title":"Measuring Mitochondrial Transmembrane Potential by TMRE Staining","volume":"2016","author":"Crowley","year":"2016","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Magi, S., Preziuso, A., Piccirillo, S., Giampieri, F., Cianciosi, D., Orciani, M., and Amoroso, S. (2021). The Neuroprotective Effect of L-Carnitine against Glyceraldehyde-Induced Metabolic Impairment: Possible Implications in Alzheimer\u2019s Disease. Cells, 10.","DOI":"10.3390\/cells10082109"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"98","DOI":"10.2144\/000113610","article-title":"Mitochondrial membrane potential probes and the proton gradient: A practical usage guide","volume":"50","author":"Perry","year":"2011","journal-title":"BioTechniques"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1016\/S0006-3495(00)76809-3","article-title":"Estimating intracellular calcium concentrations and buffering without wavelength ratioing","volume":"78","author":"Maravall","year":"2000","journal-title":"Biophys. J."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Rao, I.Y., Hanson, L.R., Johnson, J.C., Rosenbloom, M.H., and Frey, W.H. (2022). Brain Glucose Hypometabolism and Iron Accumulation in Different Brain Regions in Alzheimer\u2019s and Parkinson\u2019s Diseases. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050551"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e70294","DOI":"10.1111\/jnc.70294","article-title":"The Energetic Collapse of the Alzheimer\u2019s Brain: Metabolic Inflexibility Across Cells and Networks","volume":"169","author":"Constantino","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s10571-025-01555-z","article-title":"Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration","volume":"45","author":"Na","year":"2025","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Wang, R., Peng, S., Zhu, J., Xu, Y., Wang, M., Zhang, L., Qiu, Y., Hou, D., Wang, Q., and Liu, R. (2025). Innovations in Alzheimer\u2019s disease diagnostic technologies: Clinical prospects of novel biomarkers, multimodal integration, and non-invasive detection. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1651708"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s Association Workgroup","volume":"20","author":"Jack","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1111\/j.1476-5381.2012.02057.x","article-title":"Alzheimer\u2019s disease, \u03b2-amyloid, glutamate, NMDA receptors and memantine\u2014Searching for the connections","volume":"167","author":"Danysz","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_74","first-page":"940603","article-title":"Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: Implications for Alzheimer\u2019s disease","volume":"2013","author":"Perry","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1089\/ars.2021.0177","article-title":"Altered Metabolism in Alzheimer Disease Brain: Role of Oxidative Stress","volume":"36","author":"Rummel","year":"2022","journal-title":"Antioxid. Redox Signal."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.ccell.2014.12.006","article-title":"Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth","volume":"27","author":"Jin","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.expneurol.2008.04.005","article-title":"The l-amino acid carrier inhibitor 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) reduces l-dopa-elicited responses in dopaminergic neurons of the substantia nigra pars compacta","volume":"212","author":"Sebastianelli","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"14091","DOI":"10.1016\/S0021-9258(18)66985-6","article-title":"beta-2-Aminobicyclo-(2.2.1)-heptane-2-carboxylic acid. A new activator of glutaminase in intact rat liver mitochondria","volume":"261","author":"Zaleski","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.cell.2006.06.059","article-title":"Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer\u2019s Disease-Linked Mutations","volume":"126","author":"Tu","year":"2006","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00401-017-1733-7","article-title":"Post-Translational Remodeling of Ryanodine Receptor Induces Calcium Leak Leading to Alzheimer\u2019s Disease-like Pathologies and Cognitive Deficits","volume":"134","author":"Lacampagne","year":"2017","journal-title":"Acta Neuropathol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/5\/667\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T17:13:07Z","timestamp":1779383587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/5\/667"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":80,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["biom16050667"],"URL":"https:\/\/doi.org\/10.3390\/biom16050667","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}