Mikroglijalna disfunkcija i kognitivno oštećenje u animalnim modelima dijabetesa tipa 2: sistematski pregled koji povezuje dijabetes i ranu neurodegeneraciju
Sažetak
Dijabetes tipa 2 (T2D) usko je povezan sa kognitivnim oštećenjem i povećanim rizikom od demencije. Smatra se da rane neuropatološke promene u T2D obuhvataju neuroinflamatorne procese, što ukazuje da funkcija mikroglije u dijabetičnom mozgu može biti narušena ili pomerena ka maladaptivno aktiviranom stanju. Rastući broj dokaza implicira disfunkciju mikroglije kao ključni mehanizam u osnovi kognitivnog oštećenja povezanog sa T2D. Promene u prostornom učenju, memoriji i izvršnim funkcijama prate funkcionalne i fenotipske alteracije mikroglijalnih ćelija, naročito unutar hipokampalnih i kortikalnih moždanih krugova. Istovremeno se javljaju rane neurodegenerativne promene, uključujući gubitak neurona, sinaptičke alteracije, akumulaciju Aβ i p-Tau, kao i transkriptomski potpis karakterističan za Alchajmerovu bolest (AD) u vulnerabilnim moždanim regionima. Starenjem mikroglija sve značajnije doprinosi neurodegeneraciji, jer njene regulatorne interakcije sa neuronima slabe, što pogoduje njenoj trajnoj aktivaciji. Ovaj mini sistematski pregled ima za cilj da sintetizuje aktuelne in vivo nalaze o odnosu između kognitivnog oštećenja i promena mikroglije u animalnim modelima T2D i da razgraniči osnovne patofiziološke mehanizme koji povezuju hronični metabolički stres, disfunkciju mikroglije i rane neurodegenerativne promene. Dodatno, nastoji da istakne kako ovi mehanistički putevi, koji obuhvataju signalizaciju mikroglije, inflamatorne medijatore i metaboličko reprogramiranje, mogu predstavljati obećavajuće terapijske targete za prevenciju ili ublažavanje neurodegeneracije povezane sa dijabetesom.
Reference
Hayden MR. Brain Injury: Response to Injury Wound-Healing Mechanisms and Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus. Medicina. 2023;59(7):1337.
Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol. 2018;14(10):591–604.
De Felice FG. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J Clin Invest. 2013;123(2):531–9.
Zhang Y, Yuan Y, Zhang J, Zhao Y, Zhang Y, Fu J. Astragaloside IV supplementation attenuates cognitive impairment by inhibiting neuroinflammation and oxidative stress in type 2 diabetic mice. Front Aging Neurosci. 2022;14:1004557.
Sood A, Fernandes V, Preeti K, Rajan S, Khatri DK, Singh SB. S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway. Int Immunopharmacol. 2024;126:111278.
Gao X, Sun H, Wei Y, Niu J, Hao S, Sun H, et al. Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice. Phytomedicine. 2024;131:155805.
Aranđelović J, Ivanović J, Batinić B, Mirković K, Matović BD, Savić MM. Sucrose binge-eating and increased anxiety-like behavior in Sprague–Dawley rats exposed to repeated LPS administration followed by chronic mild unpredictable stress. Sci Rep. 2024;14(1):22569.
Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6(7):e1000097.
Zhang PA, Sun Q, Li YC, Weng RX, Wu R, Zhang HH, et al. Overexpression of Purinergic P2X4 Receptors in Hippocampus Rescues Memory Impairment in Rats with Type 2 Diabetes. Neurosci Bull. 2020;36(7):719–32.
Srodulski S, Sharma S, Bachstetter AB, Brelsfoard JM, Pascual C, Xie XS, et al. Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Mol Neurodegeneration. 2014;9(1):30.
Busquets O, Ettcheto M, Eritja À, Espinosa-Jiménez T, Verdaguer E, Olloquequi J, et al. c-Jun N-terminal Kinase 1 ablation protects against metabolic-induced hippocampal cognitive impairments. J Mol Med. 2019;97(12):1723–33.
Hiramoto K, Imai M, Tanaka S, Ooi K. Dementia Is Induced via the AGEs/Iba1/iNOS Pathway in Aged KK-Ay/Tajcl Mice. Life. 2023 Jul 11;13(7):1540.
Infante‐Garcia C, Jose Ramos‐Rodriguez J, Marin‐Zambrana Y, Teresa Fernandez‐Ponce M, Casas L, Mantell C, et al. Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model. Brain Pathol. 2017;27(4):499–507.
Tian L, Li X, Zeng X, Han Y, Qian M, Ye Y, et al. Increased Thyroid Hormone Action Alleviates Hippocampal Damage by Downregulating Neuronal Type I Interferon Signaling/Necroptosis in Diabetes-Associated Cognitive Dysfunction. Thyroid®. 2024;34(10):1292–307.
Sánchez-Sarasúa S, Moustafa S, García-Avilés Á, López-Climent MF, Gómez-Cadenas A, Olucha-Bordonau FE, et al. The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation. Nutr Metab (Lond). 2016;13(1):73.
Spoelder M, Bright Y, Morrison MC, Van Kempen V, De Groodt L, Begalli M, et al. Cognitive Performance during the Development of Diabetes in the Zucker Diabetic Fatty Rat. Cells. 2023;12(20):2463.
Zhang Y, Hu X, Chen S, Hua F, Zeng Z. Unveiling the impact of ferroptosis on diabetes‐associated cognitive decline through comprehensive single‐cell RNA sequencing and experimental studies. The FEBS Journal. 2025;292(14):3795–813.
Yu SX, Yu HD, Wang YF, Yao TF, Lv SZ, Wang YC, et al. Th22 cells promote the transition from homeostatic to reactive microglia in diabetic encephalopathy. Acta Diabetol. 2024;62(5):633–50.
Wang X, Jiang H, Wang H, Zhao C, Ba X. Astragaloside IV improves cognitive impairment in diabetes by inhibiting calpain-1/NLRP3 mediated microglial activation. Int Immunopharmacol. 2025;167:115682.
Sun H, Gao X, Niu J, Chen P, He S, Xu S, et al. AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin. eNeuro. 2024;11(12):310–24.
Xu J, Xie L, Yin J, Shi X, Dong K, Tao J, et al. A High-Carbohydrate Diet Induces Cognitive Impairment and Promotes Amyloid Burden and Tau Phosphorylation via PI3K/Akt/GSK-3β Pathway in db/db Mice. Biomedicines. 2024;12(8):1701.
Elzinga SE, Guo K, Turfah A, Henn RE, Webber‐Davis IF, Hayes JM, et al. Metabolic stress and age drive inflammation and cognitive decline in mice and humans. Alzheimers Dement. 2025;21(3):e70060.
Sood A, Fernandes V, Preeti K, Khot M, Khatri DK, Singh SB. Fingolimod Alleviates Cognitive Deficit in Type 2 Diabetes by Promoting Microglial M2 Polarization via the pSTAT3-jmjd3 Axis. Mol Neurobiol. 2023;60(2):901–22.
Ni W, Niu Y, Cao S, Fan C, Fan J, Zhu L, et al. Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling. J Neuroinflammation. 2024;21(1):166.
Chen X, Fan M, Xiao Z, Xiong X. Dapagliflozin Improves High‐Fat Diet‐Induced Cognitive Impairment in Female Mice. Brain Behav. 2025;15(2):e70361.
Zhang J, Zhang Y, Yuan Y, Liu L, Zhao Y, Wang X. Gut Microbiota Alteration Is Associated With Cognitive Deficits in Genetically Diabetic (Db/db) Mice During Aging. Front Aging Neurosci. 2022;13:815562.
Kesner RP, Hunsaker MR. The temporal attributes of episodic memory. Behav Brain Res. 2010;215(2):299–309.
Yong S, Yuhan Z, Shanshan C, Xin W, Leilei S, Liu J. The effect and mechanism of palmar ginseng in type 2 diabetic cognitive impairment. Heliyon. 2024;10(12):e32525.
Yang Y, Wang JZ. From Structure to Behavior in Basolateral Amygdala-Hippocampus Circuits. Front Neural Circuits. 2017;11:86.
Hierro-Bujalance C, Infante-Garcia C, Del Marco A, Herrera M, Carranza-Naval MJ, Suarez J, et al. Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes. Alz Res Therapy. 2020;12(1):40.
Carranza-Naval MJ, Del Marco A, Hierro-Bujalance C, Alves-Martinez P, Infante-Garcia C, Vargas-Soria M, et al. Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer’s Disease and Type 2 Diabetes. Front Aging Neurosci. 2021;13:741923.
De Luca SN, Soch A, Sominsky L, Nguyen TX, Bosakhar A, Spencer SJ. Glial remodeling enhances short-term memory performance in Wistar rats. J Neuroinflammation. 2020;17(1):52.
Yang X, Xu Y, Gao W, Wang L, Zhao X, Liu G, et al. Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro. Front Neurosci. 2022;16:1036872.
Preeti K, Fernandes V, Sood A, Khan I, Khatri DK, Singh SB. Correction to: Necrostatin-1 S mitigates type-2 diabetes-associated cognitive decrement and lipotoxicity-induced neuro-microglia changes through p-RIPK-RIPK3-p-MLKL axis. Metab Brain Dis. 2023;38(6):2193–6.
Xu H, Tian X, Wang Y, Lin J, Zhu B, Zhao C, et al. Exercise Promotes Hippocampal Neurogenesis in T2DM Mice via Irisin/TLR4/MyD88/NF-κB-Mediated Neuroinflammation Pathway. Biology. 2024;13(10):809.
Torres-Rodriguez O, Ortiz-Nazario E, Rivera-Escobales Y, Velazquez B, Colón M, Porter JT. Sex-dependent effects of microglial reduction on impaired fear extinction induced by single prolonged stress. Front Behav Neurosci. 2023;16:1014767.
Santiago JA, Karthikeyan M, Lackey M, Villavicencio D, Potashkin JA. Diabetes: a tipping point in neurodegenerative diseases. Trends Mol Med. 2023;29(12):1029–44.
Nazareth AMD. Type 2 diabetes mellitus in the pathophysiology of Alzheimer’s disease. Dement neuropsychol. 2017;11(2):105–13.
De Felice FG, Ferreira ST. Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease. Diabetes. 2014;63(7):2262–72.
Van Sloten TT, Sedaghat S, Carnethon MR, Launer LJ, Stehouwer CDA. Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol. 2020;8(4):325–36.
Vargas-Soria M, García-Alloza M, Corraliza-Gómez M. Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies. J Neuroinflammation. 2023;20(1):57.
Mecca C, Giambanco I, Donato R, Arcuri C. Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes. IJMS. 2018;19(1):318.
Ana B. Aged-Related Changes in Microglia and Neurodegenerative Diseases: Exploring the Connection. Biomedicines. 2024;12(8):1737. doi: 10.3390/biomedicines12081737.
Chen C, Wu S, Hong Z, Chen X, Shan X, Fischbach S, et al. Chronic hyperglycemia regulates microglia polarization through ERK5. Aging. 2019;11(2):697–706.
Zhang J, Lin X, Huang Q, Fu Z, Huang Y, Chen Z, et al. The overexpression of miR-146a in hippocampal microglia via IRAK1/TRAF6/NF-κB pathway improves cognitive function in diabetic mice. Exp Neurol. 2025;391:115291.
Cui Y, Yang M, Wang Y, Ren J, Lin P, Cui C, et al. Melatonin prevents diabetes‐associated cognitive dysfunction from microglia‐mediated neuroinflammation by activating autophagy via TLR4/Akt/mTOR pathway. FASEB J. 2021;35(4):e21485.
Zhou X, Zhu Y, Gao L, Li Y, Li H, Huang C, et al. Binding of RAGE and RIPK1 induces cognitive deficits in chronic hyperglycemia‐derived neuroinflammation. CNS Neurosci Ther. 2024;30(3):e14449.
- Autori zadržavaju autorska prava i pružaju časopisu pravo prvog objavljivanja rada i licenciraju ga "Creative Commons Attribution licencom" koja omogućava drugima da dele rad, uz uslov navođenja autorstva i izvornog objavljivanja u ovom časopisu.
- Autori mogu izraditi zasebne, ugovorne aranžmane za neekskluzivnu distribuciju članka objavljenog u časopisu (npr. postavljanje u institucionalni repozitorijum ili objavljivanje u knjizi), uz navođenje da je članak izvorno objavljen u ovom časopisu.
- Autorima je dozvoljeno i podstiču se da postave objavljeni članak onlajn (npr. u institucionalni repozitorijum ili na svoju internet stranicu) pre ili tokom postupka prijave rukopisa, s obzirom da takav postupak može voditi produktivnoj razmeni ideja i ranijoj i većoj citiranosti objavljenog članka (Vidi Efekti otvorenog pristupa).