{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T13:43:22Z","timestamp":1794577402968,"version":"4.9.1"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":69,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100031541","name":"Kavli Institute for Neuroscience, Yale School of Medicine","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100031541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01034924"],"award-info":[{"award-number":["R01034924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health,United States","award":["P30AG066508"],"award-info":[{"award-number":["P30AG066508"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurodegeneration"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metabolic dysfunction contributes to the risk and progression of Alzheimer\u2019s disease (AD), yet the cellular mechanisms linking impaired insulin signaling and systemic metabolic stress to brain dysfunction remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We examined the impact of chronic high-fat, high-sugar (HFHS)-induced insulin resistance on metabolic parameters, spatial learning and memory, and in vivo glial activation and neuropathology in Alzheimer\u2019s disease knock-in mice expressing human mutant APP and wild-type (WT) tau. Single-nucleus RNA sequencing was performed to resolve cell-type-specific transcriptional responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HFHS-diet induced weight gain, hyperglycemia, and glucose intolerance in WT and AD knock-in mice as compared to control diet-fed mice. However, impaired spatial learning was observed only in AD knock-in mice on the HFHS diet, even though there was no greater amyloid-\u03b2 deposition or tau phosphorylation than in control diet AD knock-in mice. Transcriptomic profiling revealed that HFHS-fed AD mice engaged a distinct glial program, which we termed the metabolic impairment in neurodegeneration (MinD) state, characterized by upregulation of genes involved in synaptic targeting and trans-synaptic signaling shared across microglia, astrocytes, and oligodendrocytes. In parallel, we identified selective induction of the transcription factor\n                      <jats:italic>Meis2<\/jats:italic>\n                      in cortical Layer 2 inhibitory neurons, which exhibited HFHS-diet transcriptional remodeling enriched for pathways regulating vesicle release, synaptic organization, and membrane excitability. These coordinated glial and neuronal transcriptional changes were associated with reduced inhibitory synapse density in HFHS-fed AD mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Diet-induced insulin resistance in AD knock-in mice is associated with coordinated glial and inhibitory neuron transcriptional remodeling and cognitive impairment, without alteration of the classical amyloid and tau pathology present in the AD mice fed a lean diet. These findings define cellular programs linking systemic insulin metabolic dysfunction to cortical circuity vulnerability in AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-026-00946-0","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:34:22Z","timestamp":1780500862000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer\u2019s knock-in mouse phenotypes"],"prefix":"10.1186","volume":"21","author":[{"given":"LaShae","family":"Nicholson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si Jie","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejaswini","family":"Karra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habiba","family":"Abouelatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Strittmatter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"issue":"6","key":"946_CR1","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1056\/NEJMoa1215740","volume":"369","author":"PK Crane","year":"2013","unstructured":"Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540\u20138.","journal-title":"N Engl J Med"},{"key":"946_CR2","doi-asserted-by":"publisher","first-page":"4981814","DOI":"10.1155\/2020\/4981814","volume":"2020","author":"Y Sun","year":"2020","unstructured":"Sun Y, Ma C, Sun H, Wang H, Peng W, Zhou Z, et al. Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer\u2019s Disease. J Diabetes Res. 2020;2020:4981814.","journal-title":"J Diabetes Res"},{"key":"946_CR3","doi-asserted-by":"publisher","first-page":"105604","DOI":"10.1016\/j.neubiorev.2024.105604","volume":"159","author":"V van Gils","year":"2024","unstructured":"van Gils V, Rizzo M, Cote J, Viechtbauer W, Fanelli G, Salas-Salvado J, et al. The association of glucose metabolism measures and diabetes status with Alzheimer\u2019s disease biomarkers of amyloid and tau: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2024;159:105604.","journal-title":"Neurosci Biobehav Rev"},{"issue":"9","key":"946_CR4","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1212\/WNL.0b013e3181eee25f","volume":"75","author":"T Matsuzaki","year":"2010","unstructured":"Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010;75(9):764\u201370.","journal-title":"Neurology"},{"issue":"22","key":"946_CR5","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1212\/WNL.0b013e3181ffe4f6","volume":"75","author":"EM Schrijvers","year":"2010","unstructured":"Schrijvers EM, Witteman JC, Sijbrands EJ, Hofman A, Koudstaal PJ, Breteler MM. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology. 2010;75(22):1982\u20137.","journal-title":"Neurology"},{"issue":"6","key":"946_CR6","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1002\/oby.23761","volume":"31","author":"AB Kim","year":"2023","unstructured":"Kim AB, Arvanitakis Z. Insulin resistance, cognition, and Alzheimer disease. Obes (Silver Spring). 2023;31(6):1486\u201398.","journal-title":"Obes (Silver Spring)"},{"issue":"1","key":"946_CR7","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1093\/brain\/awac309","volume":"146","author":"M Leclerc","year":"2023","unstructured":"Leclerc M, Bourassa P, Tremblay C, Caron V, Sugere C, Emond V, et al. Cerebrovascular insulin receptors are defective in Alzheimer\u2019s disease. Brain. 2023;146(1):75\u201390.","journal-title":"Brain"},{"key":"946_CR8","doi-asserted-by":"crossref","unstructured":"Sai KKS, Erichsen JM, Gollapelli KK, Krizan I, Miller M, Damuka N, et al. First-in-human positron emission tomography study of intranasal insulin in aging and MCI. Alzheimer\u2019s & Dementia: Trans Res Clin Int. 2025;11(3):e70123.","DOI":"10.1002\/trc2.70123"},{"issue":"12","key":"946_CR9","doi-asserted-by":"publisher","first-page":"8661","DOI":"10.1002\/alz.14313","volume":"20","author":"W Wang","year":"2024","unstructured":"Wang W, Wang Q, Qi X, Gurney M, Perry G, Volkow ND, et al. Associations of semaglutide with first-time diagnosis of Alzheimer\u2019s disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimer\u2019s Dement. 2024;20(12):8661\u201372.","journal-title":"Alzheimer\u2019s Dement"},{"issue":"Suppl 3","key":"946_CR10","doi-asserted-by":"publisher","first-page":"S215","DOI":"10.2337\/diabetes.53.suppl_3.S215","volume":"53","author":"MS Winzell","year":"2004","unstructured":"Winzell MS, Ahren B. The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes. 2004;53(Suppl 3):S215\u20139.","journal-title":"Diabetes"},{"issue":"6","key":"946_CR11","doi-asserted-by":"publisher","first-page":"E1323","DOI":"10.1152\/ajpendo.90617.2008","volume":"295","author":"S Andrikopoulos","year":"2008","unstructured":"Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J. Evaluating the glucose tolerance test in mice. Am J Physiol Endocrinol Metab. 2008;295(6):E1323\u201332.","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"5","key":"946_CR12","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nn.3697","volume":"17","author":"T Saito","year":"2014","unstructured":"Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al. Single App knock-in mouse models of Alzheimer\u2019s disease. Nat Neurosci. 2014;17(5):661\u20133.","journal-title":"Nat Neurosci"},{"key":"946_CR13","doi-asserted-by":"crossref","unstructured":"Chiasseu M, Fesharaki-Zadeh A, Saito T, Saido TC, Strittmatter SM. Gene-environment interaction promotes Alzheimer\u2019s risk as revealed by synergy of repeated mild traumatic brain injury and mouse knock-in. Neurobiol Dis. 2020;145.","DOI":"10.1016\/j.nbd.2020.105059"},{"issue":"34","key":"946_CR14","doi-asserted-by":"publisher","first-page":"12754","DOI":"10.1074\/jbc.RA119.009487","volume":"294","author":"T Saito","year":"2019","unstructured":"Saito T, Mihira N, Matsuba Y, Sasaguri H, Hashimoto S, Narasimhan S, et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J Biol Chem. 2019;294(34):12754\u201365.","journal-title":"J Biol Chem"},{"issue":"647","key":"946_CR15","doi-asserted-by":"publisher","first-page":"eabi8593","DOI":"10.1126\/scitranslmed.abi8593","volume":"14","author":"J Spurrier","year":"2022","unstructured":"Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, et al. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci Transl Med. 2022;14(647):eabi8593.","journal-title":"Sci Transl Med"},{"issue":"1","key":"946_CR16","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/s13195-023-01345-z","volume":"15","author":"A Stoner","year":"2023","unstructured":"Stoner A, Fu L, Nicholson L, Zheng C, Toyonaga T, Spurrier J, et al. Neuronal transcriptome, tau and synapse loss in Alzheimer\u2019s knock-in mice require prion protein. Alzheimers Res Ther. 2023;15(1):201.","journal-title":"Alzheimers Res Ther"},{"issue":"1","key":"946_CR17","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41398-022-02067-w","volume":"12","author":"A Amelianchik","year":"2022","unstructured":"Amelianchik A, Sweetland-Martin L, Norris EH. The effect of dietary fat consumption on Alzheimer\u2019s disease pathogenesis in mouse models. Translational Psychiatry. 2022;12(1):293.","journal-title":"Translational Psychiatry"},{"issue":"3","key":"946_CR18","doi-asserted-by":"publisher","first-page":"977","DOI":"10.3233\/JAD-230118","volume":"97","author":"J Valentin-Escalera","year":"2024","unstructured":"Valentin-Escalera J, Leclerc M, Calon F, Panza F. High-Fat Diets in Animal Models of Alzheimer\u2019s Disease: How Can Eating Too Much Fat Increase Alzheimer\u2019s Disease Risk? J Alzheimer\u2019s Disease. 2024;97(3):977\u20131005.","journal-title":"J Alzheimer\u2019s Disease"},{"issue":"10","key":"946_CR19","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.3390\/nu4101367","volume":"4","author":"B Omar","year":"2012","unstructured":"Omar B, Pacini G, Ahren B. Differential development of glucose intolerance and pancreatic islet adaptation in multiple diet induced obesity models. Nutrients. 2012;4(10):1367\u201381.","journal-title":"Nutrients"},{"issue":"9\u201310","key":"946_CR20","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1242\/dmm.006239","volume":"3","author":"JE Ayala","year":"2010","unstructured":"Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, et al. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech. 2010;3(9\u201310):525\u201334.","journal-title":"Dis Model Mech"},{"issue":"1","key":"946_CR21","doi-asserted-by":"publisher","first-page":"102133","DOI":"10.1016\/j.xpro.2023.102133","volume":"4","author":"H Chen","year":"2023","unstructured":"Chen H, Liu J, Shi GP, Zhang X. Protocol for in vivo and ex vivo assessment of hyperglycemia and islet function in diabetic mice. STAR Protoc. 2023;4(1):102133.","journal-title":"STAR Protoc"},{"key":"946_CR22","doi-asserted-by":"crossref","unstructured":"Spurrier J, Nicholson L, Fang XTT, Stoner AJ, Toyonaga T, Holden D, et al. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci Transl Med. 2022;14(647).","DOI":"10.1126\/scitranslmed.abi8593"},{"issue":"1","key":"946_CR23","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf FA, Angerer P, Theis FJ. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 2018;19(1):15.","journal-title":"Genome Biol"},{"issue":"1","key":"946_CR24","doi-asserted-by":"publisher","first-page":"5233","DOI":"10.1038\/s41598-019-41695-z","volume":"9","author":"VA Traag","year":"2019","unstructured":"Traag VA, Waltman L, van Eck NJ. From Louvain to Leiden: guaranteeing well-connected communities. Sci Rep. 2019;9(1):5233.","journal-title":"Sci Rep"},{"issue":"2","key":"946_CR25","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41587-021-01206-w","volume":"40","author":"A Gayoso","year":"2022","unstructured":"Gayoso A, Lopez R, Xing G, Boyeau P, Valiollah Pour Amiri V, Hong J, et al. A Python library for probabilistic analysis of single-cell omics data. Nat Biotechnol. 2022;40(2):163\u20136.","journal-title":"Nat Biotechnol"},{"issue":"11","key":"946_CR26","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498\u2013504.","journal-title":"Genome Res"},{"issue":"8","key":"946_CR27","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","volume":"25","author":"G Bindea","year":"2009","unstructured":"Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25(8):1091\u20133.","journal-title":"Bioinformatics"},{"issue":"D1","key":"946_CR28","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","volume":"49","author":"D Szklarczyk","year":"2021","unstructured":"Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets. Nucleic Acids Res. 2021;49(D1):D605\u201312.","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"946_CR29","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease. Cell. 2017;169(7):1276\u2013e9017.","journal-title":"Cell"},{"key":"946_CR30","doi-asserted-by":"crossref","unstructured":"Fumagalli L, Nazlie Mohebiany A, Premereur J, Polanco Miquel P, Bijnens B, Van de Walle P, et al. Microglia heterogeneity, modeling and cell-state annotation in development and neurodegeneration. Nat Neurosci. 2025.","DOI":"10.1038\/s41593-025-01931-4"},{"issue":"3","key":"946_CR31","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","volume":"47","author":"S Krasemann","year":"2017","unstructured":"Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017;47(3):566\u201381. e9.","journal-title":"Immunity"},{"issue":"10","key":"946_CR32","doi-asserted-by":"publisher","first-page":"5239","DOI":"10.1007\/s12035-021-02477-9","volume":"58","author":"B Kulkarni","year":"2021","unstructured":"Kulkarni B, Kumar D, Cruz-Martins N, Sellamuthu S. Role of TREM2 in Alzheimer\u2019s Disease: A Long Road Ahead. Mol Neurobiol. 2021;58(10):5239\u201352.","journal-title":"Mol Neurobiol"},{"issue":"22","key":"946_CR33","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.1016\/j.cell.2022.09.033","volume":"185","author":"S Wang","year":"2022","unstructured":"Wang S, Sudan R, Peng V, Zhou Y, Du S, Yuede CM, et al. TREM2 drives microglia response to amyloid-\u03b2 via SYK-dependent and -independent pathways. Cell. 2022;185(22):4153\u2013e6919.","journal-title":"Cell"},{"issue":"9","key":"946_CR34","doi-asserted-by":"publisher","first-page":"992","DOI":"10.15252\/emmm.201606370","volume":"8","author":"X Xiang","year":"2016","unstructured":"Xiang X, Werner G, Bohrmann B, Liesz A, Mazaheri F, Capell A, et al. TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol Med. 2016;8(9):992\u20131004.","journal-title":"EMBO Mol Med"},{"issue":"1","key":"946_CR35","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13024-023-00599-3","volume":"18","author":"W Qiao","year":"2023","unstructured":"Qiao W, Chen Y, Zhong J, Madden BJ, Charlesworth CM, Martens YA, et al. Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology. Mol Neurodegener. 2023;18(1):8.","journal-title":"Mol Neurodegener"},{"issue":"8","key":"946_CR36","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1016\/j.neuron.2021.02.010","volume":"109","author":"S-H Lee","year":"2021","unstructured":"Lee S-H, Meilandt WJ, Xie L, Gandham VD, Ngu H, Barck KH, et al. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by \u03b2-amyloid pathology. Neuron. 2021;109(8):1283\u2013e3016.","journal-title":"Neuron"},{"issue":"4","key":"946_CR37","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.celrep.2012.02.014","volume":"1","author":"T Masuda","year":"2012","unstructured":"Masuda T, Tsuda M, Yoshinaga R, Tozaki-Saitoh H, Ozato K, Tamura T, et al. IRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype. Cell Rep. 2012;1(4):334\u201340.","journal-title":"Cell Rep"},{"issue":"10","key":"946_CR38","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.1038\/s41590-024-01962-2","volume":"25","author":"K Saeki","year":"2024","unstructured":"Saeki K, Pan R, Lee E, Kurotaki D, Ozato K. IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs. Nat Immunol. 2024;25(10):1928\u201342.","journal-title":"Nat Immunol"},{"issue":"6","key":"946_CR39","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41593-020-0624-8","volume":"23","author":"N Habib","year":"2020","unstructured":"Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimer\u2019s disease and aging. Nat Neurosci. 2020;23(6):701\u20136.","journal-title":"Nat Neurosci"},{"key":"946_CR40","doi-asserted-by":"crossref","unstructured":"Ledonne A, Mercuri NB. On the modulatory roles of neuregulins\/ErbB signaling on synaptic plasticity. Int J Mol Sci. 2019;21(1).","DOI":"10.3390\/ijms21010275"},{"key":"946_CR41","doi-asserted-by":"crossref","unstructured":"Liu J, Geraghty JR, Schram S, Cropper HC, Lei J, Loeb JA, et al. Prevention of Alzheimer pathology by blocking neuregulin signaling on microglia. eNeuro. 2023;10(11).","DOI":"10.1523\/ENEURO.0422-23.2023"},{"issue":"4","key":"946_CR42","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.neuron.2007.04.009","volume":"54","author":"RS Woo","year":"2007","unstructured":"Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron. 2007;54(4):599\u2013610.","journal-title":"Neuron"},{"issue":"7","key":"946_CR43","doi-asserted-by":"publisher","first-page":"3133","DOI":"10.1038\/s41380-023-02066-3","volume":"28","author":"R Batista-Brito","year":"2023","unstructured":"Batista-Brito R, Majumdar A, Nuno A, Ward C, Barnes C, Nikouei K, et al. Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics. Mol Psychiatry. 2023;28(7):3133\u201343.","journal-title":"Mol Psychiatry"},{"key":"946_CR44","doi-asserted-by":"crossref","unstructured":"Spahic H, Parmar P, Miller S, Emerson PC, Lechner C, St Pierre M, et al. Dysregulation of ErbB4 signaling pathway in the dorsal hippocampus after neonatal hypoxia-ischemia and late deficits in PV(+) Interneurons, synaptic plasticity and working memory. Int J Mol Sci. 2022;24(1).","DOI":"10.3390\/ijms24010508"},{"issue":"4","key":"946_CR45","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","volume":"24","author":"\u00c5 Segerstolpe","year":"2016","unstructured":"Segerstolpe \u00c5, Palasantza A, Eliasson P, Andersson E-M, Andr\u00e9asson A-C, Sun X, et al. Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes. Cell Metabol. 2016;24(4):593\u2013607.","journal-title":"Cell Metabol"},{"issue":"12","key":"946_CR46","doi-asserted-by":"publisher","first-page":"3013","DOI":"10.2337\/db17-0311","volume":"66","author":"E Ottosson-Laakso","year":"2017","unstructured":"Ottosson-Laakso E, Krus U, Storm P, Prasad RB, Oskolkov N, Ahlqvist E, et al. Glucose-Induced Changes in Gene Expression in Human Pancreatic Islets: Causes or Consequences of Chronic Hyperglycemia. Diabetes. 2017;66(12):3013\u201328.","journal-title":"Diabetes"},{"issue":"8031","key":"946_CR47","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1038\/s41586-024-07922-y","volume":"633","author":"CA Beddows","year":"2024","unstructured":"Beddows CA, Shi F, Horton AL, Dalal S, Zhang P, Ling CC, et al. Pathogenic hypothalamic extracellular matrix promotes metabolic disease. Nature. 2024;633(8031):914\u201322.","journal-title":"Nature"},{"issue":"8","key":"946_CR48","doi-asserted-by":"publisher","first-page":"3192","DOI":"10.1038\/s41380-022-01634-3","volume":"27","author":"JW Fawcett","year":"2022","unstructured":"Fawcett JW, Fyhn M, Jendelova P, Kwok JCF, Ruzicka J, Sorg BA. The extracellular matrix and perineuronal nets in memory. Mol Psychiatry. 2022;27(8):3192\u2013203.","journal-title":"Mol Psychiatry"},{"issue":"7","key":"946_CR49","doi-asserted-by":"publisher","first-page":"112788","DOI":"10.1016\/j.celrep.2023.112788","volume":"42","author":"L Lupori","year":"2023","unstructured":"Lupori L, Totaro V, Cornuti S, Ciampi L, Carrara F, Grilli E, et al. A comprehensive atlas of perineuronal net distribution and colocalization with parvalbumin in the adult mouse brain. Cell Rep. 2023;42(7):112788.","journal-title":"Cell Rep"},{"issue":"3","key":"946_CR50","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.3233\/JAD-210059","volume":"83","author":"D Barthold","year":"2021","unstructured":"Barthold D, Gibbons LE, Marcum ZA, Gray SL, Dirk Keene C, Grabowski TJ, et al. Alzheimer\u2019s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort. J Alzheimers Dis. 2021;83(3):1303\u201312.","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"946_CR51","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41392-024-01755-x","volume":"9","author":"H Dong","year":"2024","unstructured":"Dong H, Sun Y, Nie L, Cui A, Zhao P, Leung WK, et al. Metabolic memory: mechanisms and diseases. Signal Transduct Target Ther. 2024;9(1):38.","journal-title":"Signal Transduct Target Ther"},{"key":"946_CR52","doi-asserted-by":"publisher","first-page":"102383","DOI":"10.1016\/j.arr.2024.102383","volume":"99","author":"Y Peng","year":"2024","unstructured":"Peng Y, Yao SY, Chen Q, Jin H, Du MQ, Xue YH, et al. True or false? Alzheimer\u2019s disease is type 3 diabetes: Evidences from bench to bedside. Ageing Res Rev. 2024;99:102383.","journal-title":"Ageing Res Rev"},{"key":"946_CR53","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.npep.2015.08.009","volume":"54","author":"Q Xiang","year":"2015","unstructured":"Xiang Q, Zhang J, Li CY, Wang Y, Zeng MJ, Cai ZX, et al. Insulin resistance-induced hyperglycemia decreased the activation of Akt\/CREB in hippocampus neurons: Molecular evidence for mechanism of diabetes-induced cognitive dysfunction. Neuropeptides. 2015;54:9\u201315.","journal-title":"Neuropeptides"},{"issue":"3","key":"946_CR54","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1002\/ana.25826","volume":"88","author":"Z Arvanitakis","year":"2020","unstructured":"Arvanitakis Z, Wang HY, Capuano AW, Khan A, Taib B, Anokye-Danso F, et al. Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function. Ann Neurol. 2020;88(3):513\u201325.","journal-title":"Ann Neurol"},{"issue":"1","key":"946_CR55","doi-asserted-by":"publisher","first-page":"F214","DOI":"10.1152\/ajprenal.00204.2005","volume":"290","author":"SB Gurley","year":"2006","unstructured":"Gurley SB, Clare SE, Snow KP, Hu A, Meyer TW, Coffman TM. Impact of genetic background on nephropathy in diabetic mice. Am J Physiol Ren Physiol. 2006;290(1):F214\u201322.","journal-title":"Am J Physiol Ren Physiol"},{"issue":"15","key":"946_CR56","doi-asserted-by":"publisher","first-page":"7036","DOI":"10.1073\/pnas.1000645107","volume":"107","author":"S Takeda","year":"2010","unstructured":"Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and A\u03b2 deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci. 2010;107(15):7036\u201341.","journal-title":"Proc Natl Acad Sci"},{"issue":"3","key":"946_CR57","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/npr2.12257","volume":"42","author":"W Wang","year":"2022","unstructured":"Wang W, Tanokashira D, Shibayama Y, Tsuji R, Maruyama M, Kuroiwa C, et al. Effects of high-fat diet on nutrient metabolism and cognitive functions in young APPKINL-G-F\/NL-G-F mice. Neuropsychopharm Rep. 2022;42(3):272\u201380.","journal-title":"Neuropsychopharm Rep"},{"issue":"7953","key":"946_CR58","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41586-023-05788-0","volume":"615","author":"X Chen","year":"2023","unstructured":"Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023;615(7953):668\u201377.","journal-title":"Nature"},{"issue":"8","key":"946_CR59","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1016\/j.cell.2024.02.020","volume":"187","author":"CC Escoubas","year":"2024","unstructured":"Escoubas CC, Dorman LC, Nguyen PT, Lagares-Linares C, Nakajo H, Anderson SR, et al. Type-I-interferon-responsive microglia shape cortical development and behavior. Cell. 2024;187(8):1936\u2013e5424.","journal-title":"Cell"},{"issue":"1","key":"946_CR60","doi-asserted-by":"publisher","first-page":"17995","DOI":"10.1038\/s41598-020-75057-x","volume":"10","author":"M Yanaizu","year":"2020","unstructured":"Yanaizu M, Washizu C, Nukina N, Satoh JI, Kino Y. CELF2 regulates the species-specific alternative splicing of TREM2. Sci Rep. 2020;10(1):17995.","journal-title":"Sci Rep"},{"issue":"4","key":"946_CR61","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.3233\/JAD-215602","volume":"87","author":"BC Shaw","year":"2022","unstructured":"Shaw BC, Snider HC, Turner AK, Zajac DJ, Simpson JF, Estus S. An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain. J Alzheimers Dis. 2022;87(4):1647\u201357.","journal-title":"J Alzheimers Dis"},{"issue":"4","key":"946_CR62","doi-asserted-by":"publisher","first-page":"106375","DOI":"10.1016\/j.isci.2023.106375","volume":"26","author":"A Iguchi","year":"2023","unstructured":"Iguchi A, Takatori S, Kimura S, Muneto H, Wang K, Etani H, et al. INPP5D modulates TREM2 loss-of-function phenotypes in a beta-amyloidosis mouse model. iScience. 2023;26(4):106375.","journal-title":"iScience"},{"issue":"1","key":"946_CR63","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neuron.2014.06.007","volume":"83","author":"L Mei","year":"2014","unstructured":"Mei L, Nave KA. Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014;83(1):27\u201349.","journal-title":"Neuron"},{"issue":"1","key":"946_CR64","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/s41398-021-01485-6","volume":"11","author":"B Luo","year":"2021","unstructured":"Luo B, Liu Z, Lin D, Chen W, Ren D, Yu Z, et al. ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity. Transl Psychiatry. 2021;11(1):361.","journal-title":"Transl Psychiatry"},{"key":"946_CR65","doi-asserted-by":"crossref","unstructured":"Santiago-Marrero I, Liu F, Wang H, Arzola EP, Xiong WC, Mei L. Energy expenditure homeostasis requires ErbB4, an obesity risk gene, in the paraventricular nucleus. eNeuro. 2023;10(9).","DOI":"10.1523\/ENEURO.0139-23.2023"},{"key":"946_CR66","doi-asserted-by":"crossref","unstructured":"Ji G, Li S, Ye L, Guan J. Gene module analysis reveals cell-type specificity and potential target genes in Autism\u2019s pathogenesis. Biomedicines. 2021;9(4).","DOI":"10.3390\/biomedicines9040410"},{"issue":"4","key":"946_CR67","doi-asserted-by":"publisher","first-page":"e12799","DOI":"10.1111\/gbb.12799","volume":"21","author":"R Pass","year":"2022","unstructured":"Pass R, Haan N, Humby T, Wilkinson LS, Hall J, Thomas KL. Selective behavioural impairments in mice heterozygous for the cross disorder psychiatric risk gene DLG2. Genes Brain Behav. 2022;21(4):e12799.","journal-title":"Genes Brain Behav"},{"issue":"3","key":"946_CR68","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1001\/jamapediatrics.2022.5629","volume":"177","author":"CS Dhanasekara","year":"2023","unstructured":"Dhanasekara CS, Ancona D, Cortes L, Hu A, Rimu AH, Robohm-Leavitt C, et al. Association Between Autism Spectrum Disorders and Cardiometabolic Diseases: A Systematic Review and Meta-analysis. JAMA Pediatr. 2023;177(3):248\u201357.","journal-title":"JAMA Pediatr"},{"issue":"9","key":"946_CR69","doi-asserted-by":"publisher","first-page":"5109","DOI":"10.1128\/MCB.18.9.5109","volume":"18","author":"GH Swift","year":"1998","unstructured":"Swift GH, Liu Y, Rose SD, Bischof LJ, Steelman S, Buchberg AM, et al. An endocrine-exocrine switch in the activity of the pancreatic homeodomain protein PDX1 through formation of a trimeric complex with PBX1b and MRG1 (MEIS2). Mol Cell Biol. 1998;18(9):5109\u201320.","journal-title":"Mol Cell Biol"},{"issue":"21","key":"946_CR70","doi-asserted-by":"publisher","first-page":"17985","DOI":"10.1074\/jbc.M100678200","volume":"276","author":"Y Liu","year":"2001","unstructured":"Liu Y, MacDonald RJ, Swift GH. DNA binding and transcriptional activation by a PDX1.PBX1b.MEIS2b trimer and cooperation with a pancreas-specific basic helix-loop-helix complex. J Biol Chem. 2001;276(21):17985\u201393.","journal-title":"J Biol Chem"},{"issue":"2","key":"946_CR71","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.ydbio.2006.06.030","volume":"300","author":"X Zhang","year":"2006","unstructured":"Zhang X, Rowan S, Yue Y, Heaney S, Pan Y, Brendolan A, et al. Pax6 is regulated by Meis and Pbx homeoproteins during pancreatic development. Dev Biol. 2006;300(2):748\u201357.","journal-title":"Dev Biol"},{"issue":"1","key":"946_CR72","doi-asserted-by":"publisher","first-page":"37","DOI":"10.2478\/enr-2023-0005","volume":"57","author":"DO Krasnytska","year":"2023","unstructured":"Krasnytska DO, Viletska YM, Minchenko DO, Khita OO, Tsymbal DO, Cherednychenko AA, et al. ERN1 dependent impact of glucose and glutamine deprivations on PBX3, PBXIP1, PAX6, MEIS1, and MEIS2 genes expression in U87 glioma cells. Endocr Regul. 2023;57(1):37\u201347.","journal-title":"Endocr Regul"},{"key":"946_CR73","doi-asserted-by":"publisher","first-page":"858582","DOI":"10.3389\/fnmol.2022.858582","volume":"15","author":"A Biel","year":"2022","unstructured":"Biel A, Castanza AS, Rutherford R, Fair SR, Chifamba L, Wester JC, et al. AUTS2 Syndrome: Molecular Mechanisms and Model Systems. Front Mol Neurosci. 2022;15:858582.","journal-title":"Front Mol Neurosci"},{"key":"946_CR74","doi-asserted-by":"crossref","unstructured":"Pan C, Liu Y, Wang L, Fan WY, Ni Y, Zhang X, et al. The Kv2.2 channel mediates the inhibition of prostaglandin E2 on glucose-stimulated insulin secretion in pancreatic beta-cells. Elife. 2025;13.","DOI":"10.7554\/eLife.97234"},{"issue":"3","key":"946_CR75","doi-asserted-by":"publisher","first-page":"108235","DOI":"10.1016\/j.jbc.2025.108235","volume":"301","author":"O Benner","year":"2025","unstructured":"Benner O, Karr CH, Quintero-Gonzalez A, Tamkun MM, Chanda S. The Shab family potassium channels are highly enriched at the presynaptic terminals of human neurons. J Biol Chem. 2025;301(3):108235.","journal-title":"J Biol Chem"},{"issue":"2","key":"946_CR76","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1007\/s12264-021-00773-x","volume":"38","author":"Z Li","year":"2022","unstructured":"Li Z, Dong W, Zhang X, Lu JM, Mei YA, Hu C. Protein Kinase C Controls the Excitability of Cortical Pyramidal Neurons by Regulating Kv2.2 Channel Activity. Neurosci Bull. 2022;38(2):135\u201348.","journal-title":"Neurosci Bull"},{"issue":"3","key":"946_CR77","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nrneurol.2017.185","volume":"14","author":"SE Arnold","year":"2018","unstructured":"Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168\u201381.","journal-title":"Nat Rev Neurol"},{"issue":"9","key":"946_CR78","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1001\/jamaneurol.2020.1840","volume":"77","author":"S Craft","year":"2020","unstructured":"Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol. 2020;77(9):1099\u2013109.","journal-title":"JAMA Neurol"},{"issue":"2","key":"946_CR79","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1007\/s11357-013-9592-1","volume":"36","author":"LL Du","year":"2014","unstructured":"Du LL, Xie JZ, Cheng XS, Li XH, Kong FL, Jiang X, et al. Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi. Age (Dordr). 2014;36(2):613\u201323.","journal-title":"Age (Dordr)"},{"key":"946_CR80","doi-asserted-by":"publisher","first-page":"9","DOI":"10.4236\/aar.2016.51002","volume":"05","author":"IJ Martins","year":"2016","unstructured":"Martins IJ. Anti-aging genes improve appetite regulation and reverse cell senescence and apoptosis in global populations. Adv Aging Res. 2016;05:9\u201326.","journal-title":"Adv Aging Res"},{"key":"946_CR81","unstructured":"Martins IJ, editor. Appetite regulation and the peripheral sink amyloid beta clearance pathway in diabetes and Alzheimer\u2019s disease. 2019."},{"issue":"3","key":"946_CR82","doi-asserted-by":"publisher","first-page":"953","DOI":"10.3233\/JAD-161205","volume":"57","author":"ML Alosco","year":"2017","unstructured":"Alosco ML, Duskin J, Besser LM, Martin B, Chaisson CE, Gunstad J, et al. Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer\u2019s Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer\u2019s Coordinating Center Data Set. J Alzheimers Dis. 2017;57(3):953\u201368.","journal-title":"J Alzheimers Dis"},{"issue":"2","key":"946_CR83","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.18632\/aging.102738","volume":"12","author":"Z Sun","year":"2020","unstructured":"Sun Z, Wang ZT, Sun FR, Shen XN, Xu W, Ma YH, et al. Late-life obesity is a protective factor for prodromal Alzheimer\u2019s disease: a longitudinal study. Aging. 2020;12(2):2005\u201317.","journal-title":"Aging"}],"container-title":["Molecular Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13024-026-00946-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-026-00946-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-026-00946-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:17:58Z","timestamp":1786429078000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13024-026-00946-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":83,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["946"],"URL":"https:\/\/doi.org\/10.1186\/s13024-026-00946-0","relation":{},"ISSN":["1750-1326"],"issn-type":[{"value":"1750-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]},"assertion":[{"value":"12 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"44"}}