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Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP\/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP\/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin\u2019s effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2\u2019s potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity.<\/jats:p>","DOI":"10.3390\/ijms252111689","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T06:55:37Z","timestamp":1730357737000},"page":"11689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Amino Acid Compound 2 (AAC2) Treatment Counteracts Insulin-Induced Synaptic Gene Expression and Seizure-Related Mortality in a Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Zhijie","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7780-4961","authenticated-orcid":false,"given":"Aejin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Department of Food and Nutrition, Myongji University, 116 Myongji-ro, Cheoin-gu, Yongin-si 17058, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagarika","family":"Taneja","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianbo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Blakeslee","sequence":"additional","affiliation":[{"name":"Department of Horticulture and Crop Science, Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Townsend","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, OH 43210, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2449-2591","authenticated-orcid":false,"given":"Ouliana","family":"Ziouzenkova","sequence":"additional","affiliation":[{"name":"Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/S0140-6736(11)60813-1","article-title":"The global obesity pandemic: Shaped by global drivers and local environments","volume":"378","author":"Swinburn","year":"2011","journal-title":"Lancet"},{"key":"ref_2","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2016). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet, 387, 1513\u20131530."},{"key":"ref_3","unstructured":"GBD 2019 Dementia Forecasting Collaborators (2022). 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":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"474","DOI":"10.2337\/diabetes.53.2.474","article-title":"Increased risk of type 2 diabetes in Alzheimer disease","volume":"53","author":"Janson","year":"2004","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S1474-4422(05)70284-2","article-title":"Risk of dementia in diabetes mellitus: A systematic review","volume":"5","author":"Biessels","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/978-981-13-3540-2_4","article-title":"The Full Spectrum of Alzheimer\u2019s Disease Is Rooted in Metabolic Derangements That Drive Type 3 Diabetes","volume":"1128","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kumar, V., Kim, S.H., and Bishayee, K. (2022). Dysfunctional Glucose Metabolism in Alzheimer\u2019s Disease Onset and Potential Pharmacological Interventions. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179540"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41574-018-0048-7","article-title":"Cognitive decline and dementia in diabetes mellitus: Mechanisms and clinical implications","volume":"14","author":"Biessels","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S1474-4422(17)30044-3","article-title":"Epileptic activity in Alzheimer\u2019s disease: Causes and clinical relevance","volume":"16","author":"Vossel","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1016\/j.psyneuen.2013.05.010","article-title":"Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice","volume":"38","author":"Ortiz","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3892\/mmr.2012.1186","article-title":"mTOR and tau phosphorylated proteins in the hippocampal tissue of rats with type 2 diabetes and Alzheimer\u2019s disease","volume":"7","author":"Ma","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s40336-013-0026-y","article-title":"Glucose metabolism in normal aging and Alzheimer\u2019s disease: Methodological and physiological considerations for PET studies","volume":"1","author":"Mosconi","year":"2013","journal-title":"Clin. Transl. Imaging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e149","DOI":"10.1038\/emm.2015.3","article-title":"Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome","volume":"47","author":"Kim","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.ajcnut.2023.01.002","article-title":"Could Alzheimer\u2019s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?","volume":"117","author":"Johnson","year":"2023","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sanabria-Diaz, G., Martinez-Montes, E., Melie-Garcia, L., and Alzheimer\u2019s Disease Neuroimaging Initiative (2013). Glucose metabolism during resting state reveals abnormal brain networks organization in the Alzheimer\u2019s disease and mild cognitive impairment. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068860"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1177\/2045125316675579","article-title":"Lactate in the brain: An update on its relevance to brain energy, neurons, glia and panic disorder","volume":"7","author":"Riske","year":"2017","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.2337\/db16-1589","article-title":"Impaired Glutamatergic Neurotransmission in the Ventromedial Hypothalamus May Contribute to Defective Counterregulation in Recurrently Hypoglycemic Rats","volume":"66","author":"Chowdhury","year":"2017","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1093\/brain\/awac037","article-title":"AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures","volume":"145","author":"Salvati","year":"2022","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1001\/jamaneurol.2021.3310","article-title":"Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial","volume":"78","author":"Vossel","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nrd.2015.36","article-title":"Pursuit of a perfect insulin","volume":"15","author":"Zaykov","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1007\/s11910-012-0297-0","article-title":"Insulin: An emerging treatment for Alzheimer\u2019s disease dementia?","volume":"12","author":"Morris","year":"2012","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"146474","DOI":"10.1016\/j.brainres.2019.146474","article-title":"Low-dose intranasal insulin improves cognitive function and suppresses the development of epilepsy","volume":"1726","author":"Peng","year":"2020","journal-title":"Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, A., Sun, Y., Lin, T., Song, N.J., Mason, M.L., Leung, J.H., Kowdley, D., Wall, J., Brunetti, A., and Fitzgerald, J. (2020). Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice. Biomaterials, 239.","DOI":"10.1016\/j.biomaterials.2020.119839"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lee, A., Mason, M.L., Lin, T., Kumar, S.B., Kowdley, D., Leung, J.H., Muhanna, D., Sun, Y., Ortega-Anaya, J., and Yu, L. (2021). Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010081"},{"key":"ref_26","first-page":"e63681","article-title":"Extracellular Glucose Depletion as an Indirect Measure of Glucose Uptake in Cells and Tissues Ex Vivo","volume":"182","author":"Kumar","year":"2022","journal-title":"J. Vis. Exp."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein misfolding, functional amyloid, and human disease","volume":"75","author":"Chiti","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14273","DOI":"10.18632\/oncotarget.15131","article-title":"Boosting brain glucose metabolism to fight neurodegeneration?","volume":"8","author":"Kofalvi","year":"2017","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e12513","DOI":"10.1111\/jne.12513","article-title":"Insulin action in the brain: Roles in energy and glucose homeostasis","volume":"29","author":"Dodd","year":"2017","journal-title":"J. Neuroendocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.exger.2016.12.019","article-title":"Glucose tolerance and insulin sensitivity are impaired in APP\/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline","volume":"88","author":"Macklin","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/alzrt182","article-title":"Comprehensive behavioral characterization of an APP\/PS-1 double knock-in mouse model of Alzheimer\u2019s disease","volume":"5","author":"Webster","year":"2013","journal-title":"Alzheimers Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1023\/A:1021691918517","article-title":"Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: Lack of association with amyloid deposits","volume":"29","author":"Holcomb","year":"1999","journal-title":"Behav. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0197-4580(00)00249-9","article-title":"Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice","volume":"22","author":"Gordon","year":"2001","journal-title":"Neurobiol. Aging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cmet.2018.06.019","article-title":"CalR: A Web-Based Analysis Tool for Indirect Calorimetry Experiments","volume":"28","author":"Mina","year":"2018","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1177\/0115426592007005207","article-title":"Use of indirect calorimetry in clinical nutrition","volume":"7","author":"McClave","year":"1992","journal-title":"Nutr. Clin. Pract."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1601-183X.2006.00221.x","article-title":"Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer\u2019s disease","volume":"6","author":"Reiserer","year":"2007","journal-title":"Genes. Brain Behav."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.neurobiolaging.2021.12.009","article-title":"Both male and female APPswe\/PSEN1dE9 mice are impaired in spatial memory and cognitive flexibility at 9 months of age","volume":"113","author":"Hulshof","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2017.10.005","article-title":"Induction of innervation by encapsulated adipocytes with engineered vitamin A metabolism","volume":"192","author":"Shen","year":"2018","journal-title":"Transl. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13195-019-0558-0","article-title":"APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain","volume":"11","author":"Lefterov","year":"2019","journal-title":"Alzheimers Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gandolfo, L.C., and Speed, T.P. (2018). RLE plots: Visualizing unwanted variation in high dimensional data. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191629"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/nm.3302","article-title":"PDK1 decreases TACE-mediated alpha-secretase activity and promotes disease progression in prion and Alzheimer\u2019s diseases","volume":"19","author":"Pietri","year":"2013","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"238","DOI":"10.2174\/156720210792231840","article-title":"Spinal microvascular expression of PV-1 is associated with inflammation, perivascular astrocyte loss, and diminished EC glucose transport potential in acute SCI","volume":"7","author":"Mozer","year":"2010","journal-title":"Curr. Neurovasc Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3554","DOI":"10.18632\/aging.204029","article-title":"Claudin-5 relieves cognitive decline in Alzheimer\u2019s disease mice through suppression of inhibitory GABAergic neurotransmission","volume":"14","author":"Zhu","year":"2022","journal-title":"Aging"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Del Pozo, A., Knox, K.M., Lehmann, L., Davidson, S., Rho, S., Jayadev, S., and Barker-Haliski, M. (2023). Chronic evoked seizures in young pre-symptomatic APP\/PS1 mice induce serotonin changes and accelerate onset on Alzheimer\u2019s disease-related neurpathology. bioRxiv.","DOI":"10.1101\/2023.01.05.522897"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Li, T., and Zhu, J. (2019). Entanglement of CCR5 and Alzheimer\u2019s Disease. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00209"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Cristovao, J.S., and Gomes, C.M. (2019). S100 Proteins in Alzheimer\u2019s Disease. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00463"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"539581","DOI":"10.1155\/2010\/539581","article-title":"The S100B\/RAGE Axis in Alzheimer\u2019s Disease","volume":"2010","author":"Leclerc","year":"2010","journal-title":"Cardiovasc. Psychiatry Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/epi.13783","article-title":"Neuroinflammatory targets and treatments for epilepsy validated in experimental models","volume":"58","author":"Aronica","year":"2017","journal-title":"Epilepsia"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Liao, W., Luo, H., Ruan, Y., Mai, Y., Liu, C., Chen, J., Yang, S., Xuan, A., and Liu, J. (2022). Identification of candidate genes associated with clinical onset of Alzheimer\u2019s disease. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1060111"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14299","DOI":"10.1523\/JNEUROSCI.3383-10.2010","article-title":"Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer\u2019s disease transgenic mice","volume":"30","author":"Tampellini","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"fcab123","DOI":"10.1093\/braincomms\/fcab123","article-title":"Transcriptomic analysis of human brains with Alzheimer\u2019s disease reveals the altered expression of synaptic genes linked to cognitive deficits","volume":"3","author":"Williams","year":"2021","journal-title":"Brain Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/375488a0","article-title":"Essential functions of synapsins I and II in synaptic vesicle regulation","volume":"375","author":"Rosahl","year":"1995","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Liang, K.G., Mu, R.Z., Liu, Y., Jiang, D., Jia, T.T., and Huang, Y.J. (2019). Increased Serum S100B Levels in Patients With Epilepsy: A Systematic Review and Meta-Analysis Study. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00456"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Schwark, R., Andrade, R., and Bykhovskaia, M. (2022). Synapsin II Directly Suppresses Epileptic Seizures In Vivo. Brain Sci., 12.","DOI":"10.3390\/brainsci12030325"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1523\/JNEUROSCI.17-09-02959.1997","article-title":"Inhibition of GABAA synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus","volume":"17","author":"Tanaka","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kang, J.Q. (2021). Epileptic Mechanisms Shared by Alzheimer\u2019s Disease: Viewed via the Unique Lens of Genetic Epilepsy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137133"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"eabn2956","DOI":"10.1126\/scitranslmed.abn2956","article-title":"Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency","volume":"14","author":"Rajasekaran","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1523\/JNEUROSCI.0395-10.2010","article-title":"Memory impairment in transgenic Alzheimer mice requires cellular prion protein","volume":"30","author":"Gimbel","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41582-024-00932-4","article-title":"Epilepsy and epileptiform activity in late-onset Alzheimer disease: Clinical and pathophysiological advances, gaps and conundrums","volume":"20","author":"Kamondi","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gureviciene, I., Ishchenko, I., Ziyatdinova, S., Jin, N., Lipponen, A., Gurevicius, K., and Tanila, H. (2019). Characterization of Epileptic Spiking Associated With Brain Amyloidosis in APP\/PS1 Mice. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.01151"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1038\/sj.ijo.0801695","article-title":"Hyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans","volume":"25","author":"Kern","year":"2001","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1172\/JCI107803","article-title":"Mechanisms of seizures and coma in hypoglycemia. Evidence for a direct effect of insulin on electrolyte transport in brain","volume":"54","author":"Arieff","year":"1974","journal-title":"J. Clin. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s40263-020-00781-x","article-title":"Intranasal Insulin for Alzheimer\u2019s Disease","volume":"35","author":"Hallschmid","year":"2021","journal-title":"CNS Drugs"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1001\/jamaneurol.2020.1840","article-title":"Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial","volume":"77","author":"Craft","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neuron.2007.07.025","article-title":"Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer\u2019s disease","volume":"55","author":"Palop","year":"2007","journal-title":"Neuron"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1523\/JNEUROSCI.5215-08.2009","article-title":"Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy","volume":"29","author":"Minkeviciene","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"105.e1","DOI":"10.1016\/j.neurobiolaging.2021.03.011","article-title":"Investigation of the role of matrix metalloproteinases in the genetic etiology of Alzheimer\u2019s disease","volume":"104","author":"Hoogmartens","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.3233\/JAD-170392","article-title":"Adult-Onset Epilepsy in Presymptomatic Alzheimer\u2019s Disease: A Retrospective Study","volume":"60","author":"DiFrancesco","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.3233\/JAD-230153","article-title":"Audiogenic Seizures in the Streptozotocin-Induced Rat Alzheimer\u2019s Disease Model","volume":"94","author":"Alves","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nbt1385","article-title":"Direct multiplexed measurement of gene expression with color-coded probe pairs","volume":"26","author":"Geiss","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/msj.20159","article-title":"Transgenic mouse models of Alzheimer\u2019s disease","volume":"77","author":"Elder","year":"2010","journal-title":"Mt. Sinai J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Yang, S., Du, Y., Zhao, X., Wu, C., and Yu, P. (2022). Reducing PDK1\/Akt Activity: An Effective Therapeutic Target in the Treatment of Alzheimer\u2019s Disease. Cells, 11.","DOI":"10.3390\/cells11111735"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1111\/sji.12240","article-title":"Systemic levels of CCL2, CCL3, CCL4 and CXCL8 differ according to age, time period and season among children newly diagnosed with type 1 diabetes and their healthy siblings","volume":"80","author":"Thorsen","year":"2014","journal-title":"Scand. J. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Marciniak, E., Faivre, E., Dutar, P., Pires, C.A., Demeyer, D., Caillierez, R., Laloux, C., Buee, L., Blum, D., and Humez, S. (2015). The Chemokine MIP-1alpha\/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory. Sci. Rep., 5.","DOI":"10.1038\/srep15862"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Wolinski, P., Ksiazek-Winiarek, D., and Glabinski, A. (2022). Cytokines and Neurodegeneration in Epileptogenesis. Brain Sci., 12.","DOI":"10.3390\/brainsci12030380"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/cns.14006","article-title":"Targeting CCL5 signaling attenuates neuroinflammation after seizure","volume":"29","author":"Zhang","year":"2023","journal-title":"CNS Neurosci. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Porcher, C., Medina, I., and Gaiarsa, J.L. (2018). Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains. Front. Cell Neurosci., 12.","DOI":"10.3389\/fncel.2018.00273"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Fischer, F.P., Kasture, A.S., Hummel, T., and Sucic, S. (2022). Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.834498"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Gliwinska, A., Czubilinska-Lada, J., Wieckiewicz, G., Swietochowska, E., Badenski, A., Dworak, M., and Szczepanska, M. (2023). The Role of Brain-Derived Neurotrophic Factor (BDNF) in Diagnosis and Treatment of Epilepsy, Depression, Schizophrenia, Anorexia Nervosa and Alzheimer\u2019s Disease as Highly Drug-Resistant Diseases: A Narrative Review. Brain Sci., 13.","DOI":"10.3390\/brainsci13020163"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0166-2236(00)01869-5","article-title":"BDNF and epilepsy--the bad could turn out to be good","volume":"24","author":"Reibel","year":"2001","journal-title":"Trends Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1006\/exnr.2002.7869","article-title":"Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor","volume":"174","author":"Scharfman","year":"2002","journal-title":"Exp. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1111\/j.1460-9568.2006.05092.x","article-title":"BDNF occludes GABA receptor-mediated inhibition of GABA release in rat hippocampal CA1 pyramidal neurons","volume":"24","author":"Mizoguchi","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Johannesen, K.M., Nielsen, J., Sabers, A., Isidor, B., Kattentidt-Mouravieva, A.A., Zieglgansberger, D., Heidlebaugh, A.R., Oetjens, K.F., Vidal, A.A., and Christensen, J. (2023). The phenotypic presentation of adult individuals with SLC6A1-related neurodevelopmental disorders. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1216653"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"a005371","DOI":"10.1101\/mcs.a005371","article-title":"SLC6A1 G443D associated with developmental delay and epilepsy","volume":"6","author":"Devries","year":"2020","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/jnc.15499","article-title":"Synaptophysin-dependent synaptobrevin-2 trafficking at the presynapse-Mechanism and function","volume":"159","author":"Cousin","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.nbd.2017.08.021","article-title":"Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder","volume":"108","author":"Harper","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"20220595","DOI":"10.1515\/biol-2022-0595","article-title":"The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy","volume":"18","author":"Xin","year":"2023","journal-title":"Open Life Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"11854","DOI":"10.1523\/JNEUROSCI.1942-17.2017","article-title":"Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State","volume":"37","author":"Liu","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1002\/jnr.21173","article-title":"Long-lasting effects of elevated neonatal leptin on rat hippocampal function, synaptic proteins and NMDA receptor subunits","volume":"85","author":"Walker","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1177\/0023677215615269","article-title":"Sex differences between APPswePS1dE9 mice in A-beta accumulation and pancreatic islet function during the development of Alzheimer\u2019s disease","volume":"50","author":"Li","year":"2016","journal-title":"Lab. Anim."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Webster, S.J., Bachstetter, A.D., Nelson, P.T., Schmitt, F.A., and Van Eldik, L.J. (2014). Using mice to model Alzheimer\u2019s dementia: An overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front. Genet., 5.","DOI":"10.3389\/fgene.2014.00088"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Bhattacharya, A., Hamilton, A.M., Furberg, H., Pietzak, E., Purdue, M.P., Troester, M.A., Hoadley, K.A., and Love, M.I. (2021). An approach for normalization and quality control for NanoString RNA expression data. Brief. Bioinform., 22.","DOI":"10.1093\/bib\/bbaa163"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., and Speleman, F. (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol., 3.","DOI":"10.1186\/gb-2002-3-7-research0034"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/nbt.2931","article-title":"Normalization of RNA-seq data using factor analysis of control genes or samples","volume":"32","author":"Risso","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_96","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Carrera, I., Etcheverria, I., Fernandez-Novoa, L., Lombardi, V.R., Lakshmana, M.K., Cacabelos, R., and Vigo, C. (2015). A comparative evaluation of a novel vaccine in APP\/PS1 mouse models of Alzheimer\u2019s disease. Biomed. Res. Int., 2015.","DOI":"10.1155\/2015\/807146"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.bbr.2009.01.039","article-title":"Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe\/PS1dE9 mouse model of Alzheimer\u2019s disease","volume":"201","author":"Brown","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/nature05289","article-title":"A network dysfunction perspective on neurodegenerative diseases","volume":"443","author":"Palop","year":"2006","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14","DOI":"10.2967\/jnumed.112.114397","article-title":"The Role of Radionuclide Imaging in Epilepsy, Part 1: Sporadic Temporal and Extratemporal Lobe Epilepsy","volume":"45","author":"Kumar","year":"2017","journal-title":"J. Nucl. Med. Technol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11689\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:24:40Z","timestamp":1760113480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,30]]},"references-count":100,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111689"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111689","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,30]]}}}