A review of animal models of vascular dementia.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος:	A review of animal models of vascular dementia.
Συγγραφείς:	Song Y; Heilongjiang University of Chinese Medicine, Harbin, 150006, China., Chen Y; Department of Acupuncture Fifth, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, No. 26, Heping Road, Xiangfang District, Harbin, 150006, Heilongjiang, China. chyh9000@163.com.
Πηγή:	Molecular biology reports [Mol Biol Rep] 2026 Jul 30; Vol. 53 (1). Date of Electronic Publication: 2026 Jul 30.
Τύπος έκδοσης:	Journal Article; Review
Γλώσσα:	English
Στοιχεία περιοδικού:	Publisher: Reidel Country of Publication: Netherlands NLM ID: 0403234 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-4978 (Electronic) Linking ISSN: 03014851 NLM ISO Abbreviation: Mol Biol Rep Subsets: MEDLINE
Imprint Name(s):	Original Publication: Dordrecht, Boston, Reidel.
Ιατρικοί όροι (MeSH):	Dementia, Vascular/pathology , Dementia, Vascular/physiopathology , Dementia, Vascular/metabolism , Dementia, Vascular/etiology , Disease Models, Animal*, Brain/pathology ; Animals ; Humans
Περίληψη:	Vascular dementia (VD) is characterized by the presence of cerebrovascular lesions, specifically hemorrhagic or ischemic lesions within the brain parenchyma, with ischemic lesions being more prevalent. The resultant progressive decline in cognitive abilities and memory poses a significant challenge to public health and quality of life. Consequently, a growing number of researchers have focused on exploring the pathogenesis, prevention, and treatment strategies for VD. The establishment of suitable animal models for investigating the underlying mechanisms of VD treatment and assessing therapeutic efficacy has emerged as a focal point in this area of research. This review systematically compares the construction methods, pathological features, and behavioral phenotypes of classical and modified VD animal models, while analyzing their respective advantages and limitations. Key obstacles to clinical translation presented by the existing models are highlighted, including species differences, behavioral confounding factors, and issues related to methodological reproducibility. Furthermore, this article offers a reference framework for model selection based on various research objectives, aimed at enhancing the translational value of preclinical VD investigations. (© 2026. The Author(s), under exclusive licence to Springer Nature B.V.)
Competing Interests:	Declarations. Competing interests: The authors declare no competing interests. Clinical trial number: Not applicable.
References:	Cavanagh L, Paulsen JS (2024) Neuropsychology and vascular cognitive impairment and dementia. Neurol Clin 42(4):809–820. https://doi.org/10.1016/j.ncl.2024.05.006. (PMID: 10.1016/j.ncl.2024.05.0063934347612261353) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium (2024) A genome-wide association meta-analysis of all-cause and vascular dementia. Alzheimer’s Dementia: The J Alzheimer’s Assoc 20(9):5973-5995. https://doi.org/10.1002/alz.14115. Cai Y, Mok VCT, Markus HS (2026) Vascular dementia: World Stroke Organization fact sheet 2026. Int J Stroke 21(2):152–163. https://doi.org/10.1177/17474930251404243. (PMID: 10.1177/174749302514042434147924712831815) Morgan AE, Mc Auley MT (2024) Vascular dementia: from pathobiology to emerging perspectives. Ageing Res Rev 96:102278. https://doi.org/10.1016/j.arr.2024.102278. (PMID: 10.1016/j.arr.2024.10227838513772) Anagnostakis F, Kokkorakis M, Asvestis C et al (2025) Impact of cardiometabolic conditions on the progression from mild cognitive impairment to dementia: a large cohort study. Alzheimer’s Dementia 21(9):e70692. https://doi.org/10.1002/alz.70692. (PMID: 10.1002/alz.706924095193612434604) Qureshi D, Allen NE, Kuźma E et al (2025) Metabolic syndrome and risk of incident all-cause dementia, Alzheimer’s disease and vascular dementia: a systematic review and meta-analysis of longitudinal studies. Alzheimer’s Res Therapy. 17(1):198. https://doi.org/10.1186/s13195-025-01825-4. (PMID: 10.1186/s13195-025-01825-4) Hachinski VC, Iliff LD, Zilhka E et al (1975) Cerebral blood flow in dementia. Arch Neurol 32(9):632–637. https://doi.org/10.1001/archneur.1975.00490510088009. (PMID: 10.1001/archneur.1975.004905100880091164215) Román GC, Tatemichi TK, Erkinjuntti T et al (1993) Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43(2):250–260. https://doi.org/10.1212/wnl.43.2.250. (PMID: 10.1212/wnl.43.2.2508094895) O’Brien JT, Erkinjuntti T, Reisberg B et al (2003) Vascular cognitive impairment. The lancet. Neurology 2(2):89–98. https://doi.org/10.1016/s1474-4422(03)00305-3. (PMID: 10.1016/s1474-4422(03)00305-312849265) Iadecola C, Anrather J (2025) The immunology of stroke and dementia. Immunity 58(1):18–39. https://doi.org/10.1016/j.immuni.2024.12.008. (PMID: 10.1016/j.immuni.2024.12.0083981399211736048) Hainsworth AH, Markus HS, Schneider JA (2024) Cerebral small vessel disease, hypertension, and vascular contributions to cognitive impairment and dementia. Hypertension 81(1):75–86. https://doi.org/10.1161/HYPERTENSIONAHA.123.19943. (PMID: 10.1161/HYPERTENSIONAHA.123.1994338044814) Xiao W, Yang Y, Bai L et al (2025) Exercise-induced irisin ameliorates cognitive impairment following chronic cerebral hypoperfusion by suppressing neuroinflammation and hippocampal neuronal apoptosis. J Neuro 22(1):168. https://doi.org/10.1186/s12974-025-03493-5. (PMID: 10.1186/s12974-025-03493-5) Griffiths A, Matu J, Tang EYH et al (2024) Foods, dietary patterns, and risk of vascular dementia: a systematic review. Nutr Metab 21(1):105. https://doi.org/10.1186/s12986-024-00880-2. (PMID: 10.1186/s12986-024-00880-2) Wazny VK, Mahadevan A, Nguyen N et al (2025) Chronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice. Nat Commun 16(1):6302. https://doi.org/10.1038/s41467-025-61614-3. (PMID: 10.1038/s41467-025-61614-34062874912238411) Thangwong P, Tocharus C, Tocharus J (2025) The bidirectional role of hypoxia-inducible factor 1 alpha in vascular dementia caused by chronic cerebral hypoperfusion. Mol Neurobiol 62(8):10398–10413. https://doi.org/10.1007/s12035-025-04914-5. (PMID: 10.1007/s12035-025-04914-540205304) Bennett HC, Zhang Q, Wu YT et al (2024) Aging drives cerebrovascular network remodeling and functional changes in the mouse brain. Nat Commun 15(1):6398. https://doi.org/10.1038/s41467-024-50559-8. (PMID: 10.1038/s41467-024-50559-83908028911289283) Nanri M, Watanabe H (1999) [Availability of 2VO rats as a model for chronic cerebrovascular disease]. Nihon Yakurigaku Zasshi 113(2):85–95. https://doi.org/10.1254/fpj.113.85. (PMID: 10.1254/fpj.113.8510205783) Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10(3):267–272. https://doi.org/10.1161/01.str.10.3.267. (PMID: 10.1161/01.str.10.3.26737614) Gong S, Cai X, Wang Y et al (2024) Botch improves cognitive impairment after cerebral ischemia associated with microglia-induced A1-type astrocyte activation. Neurobiol Dis 201:106684. https://doi.org/10.1016/j.nbd.2024.106684. (PMID: 10.1016/j.nbd.2024.10668439341511) Chen YX, Yang H, Wang DS, et al (2024) Gastrodin alleviates mitochondrial dysfunction by regulating SIRT3-mediated TFAM acetylation in vascular dementia. Phytomedicine: Int J Phyto Phytopharmacol 128:155369. https://doi.org/10.1016/j.phymed.2024.155369. Zhang D, Li D, Wang X et al (2024) Urine proteomic signatures of mild hypothermia treatment in cerebral ischemia-reperfusion injury in rats. Cell Mol Neurobiol 44(1):49. https://doi.org/10.1007/s10571-024-01483-4. (PMID: 10.1007/s10571-024-01483-43883696011153299) Hainsworth AH, Allan SM, Boltze J et al (2017) Translational models for vascular cognitive impairment: a review including larger species. BMC Med 15(1):16. https://doi.org/10.1186/s12916-017-0793-9. (PMID: 10.1186/s12916-017-0793-9281188315264492) Du Y, He J, Xu Y et al (2024) SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a STAT5-PGAM5-Drp1 dependent manner. J Transl Med 22(1):788. https://doi.org/10.1186/s12967-024-05566-0. (PMID: 10.1186/s12967-024-05566-03918328011346289) Kimura S, Iwata M, Takase H et al (2025) Oxidative stress and chronic cerebral hypoperfusion: an overview from preclinical rodent models. J Cerebral Blood Flow Metab: Off J Int Soc Cerebral Blood Flow Metab 45(3):381–395. https://doi.org/10.1177/0271678X241305899. (PMID: 10.1177/0271678X241305899) Tomimoto H, Ihara M, Wakita H et al (2003) Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol 106(6):527–534. https://doi.org/10.1007/s00401-003-0749-3. (PMID: 10.1007/s00401-003-0749-313680276) Choy M, Ganesan V, Thomas DL et al (2006) The chronic vascular and haemodynamic response after permanent bilateral common carotid occlusion in newborn and adult rats. J Cereb Blood Flow Metab 26(8):1066–1075. https://doi.org/10.1038/sj.jcbfm.9600259. (PMID: 10.1038/sj.jcbfm.960025916395291) Jiwa NS, Garrard P, Hainsworth AH (2010) Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. J Neurochem 115(4):814–828. (PMID: 10.1111/j.1471-4159.2010.06958.x20731763) Du SQ, Wang XR, Xiao LY et al (2017) Molecular mechanisms of vascular dementia: what can be learned from animal models of chronic cerebral hypoperfusion? Mol Neurobiol 54(5):3670–3682. https://doi.org/10.1007/s12035-016-9915-1. (PMID: 10.1007/s12035-016-9915-127206432) Mao M, Xu Y, Zhang XY et al (2020) MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling. J Neuroinflammation 17(1):244. https://doi.org/10.1186/s12974-020-01919-w. (PMID: 10.1186/s12974-020-01919-w328194077439693) Chen X, Liu X, He H, et al (2024) Stem cell factor protects against chronic ischemic retinal injury by modulating on neurovascular unit. Biomed Pharmaco. 173:116318. https://doi.org/10.1016/j.biopha.2024.116318. Moghaddasi M, Taati M, Asadian P et al (2016) The effects of two-stage carotid occlusion on spatial memory and pro-inflammatory markers in the hippocampus of rats. J Physiol Sci. https://doi.org/10.1007/s12576-016-0474-z. (PMID: 10.1007/s12576-016-0474-z2747012910717598) Nyitrai G, Spisák T, Spisák Z et al (2018) Stepwise occlusion of the carotid arteries of the rat: MRI assessment of the effect of donepezil and hypoperfusion-induced brain atrophy and white matter microstructural changes. PLoS One 13(5):e0198265. https://doi.org/10.1371/journal.pone.0198265. (PMID: 10.1371/journal.pone.0198265298519905979036) Jing Z, Shi C, Zhu L et al (2015) Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J Cereb Blood Flow Metab 35(8):1249–1259. https://doi.org/10.1038/jcbfm.2015.55. (PMID: 10.1038/jcbfm.2015.55258539084528009) Völgyi K, Gulyássy P, Todorov MI et al (2018) Chronic cerebral hypoperfusion induced synaptic proteome changes in the rat cerebral cortex. Mol Neurobiol 55(5):4253–4266. https://doi.org/10.1007/s12035-017-0641-0. (PMID: 10.1007/s12035-017-0641-028620701) Ganzella M, de Oliveira EDA, Comassetto DD et al (2012) Effects of chronic guanosine treatment on hippocampal damage and cognitive impairment of rats submitted to chronic cerebral hypoperfusion. Neuro Sci: Off J Italian Neuro Soc Italian Soc Clin Neurophysiol 33(5):985–997. https://doi.org/10.1007/s10072-011-0872-1. (PMID: 10.1007/s10072-011-0872-1) Wu S, Huang R, Zhang R et al (2023) Gastrodin and gastrodigenin improve energy metabolism disorders and mitochondrial dysfunction to antagonize vascular dementia. Molecules 28(6):2598. https://doi.org/10.3390/molecules28062598. (PMID: 10.3390/molecules280625983698557210059574) Wei B, Wu S, Wang Z et al (2022) Comparison of cognitive performance and cardiac function between three different rat models of vascular dementia. Neuropsychiatr Dis Treat 18:19–28. https://doi.org/10.2147/NDT.S338226. (PMID: 10.2147/NDT.S338226350180988742620) Wang J, Chen W, Wang Y (2013) A ginkgo biloba extract promotes proliferation of endogenous neural stem cells in vascular dementia rats. Neural Regenera Res 8(18):1655–1662. https://doi.org/10.3969/j.issn.1673-5374.2013.18.003. (PMID: 10.3969/j.issn.1673-5374.2013.18.003) Ohta H, Nishikawa H, Kimura H et al (1997) Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats. Neuroscience 79(4):1039–1050. https://doi.org/10.1016/s0306-4522(97)00037-7. (PMID: 10.1016/s0306-4522(97)00037-79219966) Shibata M, Ohtani R, Ihara M et al (2004) White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke 35(11):2598–2603. https://doi.org/10.1161/01.STR.0000143725.19053.60. (PMID: 10.1161/01.STR.0000143725.19053.6015472111) Lim S, Lim C, Cho S (2024) Methanol extract of Ligusticum chuanxiong Hort. Rhizome ameliorates bilateral common carotid artery stenosis-induced cognitive deficit in mice by altering microglia and astrocyte activation. Front Pharmacol 15:1329895. https://doi.org/10.3389/fphar.2024.1329895. (PMID: 10.3389/fphar.2024.13298953854966710973115) Xie Y, Wang X, Liu S et al (2025) Transforming growth factor β1 protects against ischemic demyelination via regulating microglial lipid metabolism pathway. Stroke 56(6):1554–1568. https://doi.org/10.1161/STROKEAHA.124.048206. (PMID: 10.1161/STROKEAHA.124.04820640160039) Fagerli E, Jackson CW, Escobar I et al (2024) Resveratrol mitigates cognitive impairments and cholinergic cell loss in the medial septum in a mouse model of gradual cerebral hypoperfusion. Antioxidants 13(8):984. https://doi.org/10.3390/antiox13080984. (PMID: 10.3390/antiox130809843919923011351397) Yu JB, Hong C, Ren XW et al (2025) FTY720 modulating microglia-mediated cholesterol recycling via TREM2 promotes remyelination following ischemic damage. Stroke 56(7):1897–1908. https://doi.org/10.1161/STROKEAHA.124.049745. (PMID: 10.1161/STROKEAHA.124.04974540260538) Hattori Y, Enmi JI, Iguchi S et al (2016) Gradual carotid artery stenosis in mice closely replicates hypoperfusive vascular dementia in humans. J Am Heart Assoc 5(2):e002757. https://doi.org/10.1161/JAHA.115.002757. (PMID: 10.1161/JAHA.115.002757269030054802480) Lin L, Chen Y, He K et al (2024) Carotid artery vascular stenosis causes the blood-CSF barrier damage and neuroinflammation. J Neuroinflammation 21(1):220. https://doi.org/10.1186/s12974-024-03209-1. (PMID: 10.1186/s12974-024-03209-13925678311385148) Hattori Y, Enmi Jichiro, Kitamura A et al (2015) A novel mouse model of subcortical infarcts with dementia. J Neurosci 35(9):3915–3928. https://doi.org/10.1523/JNEUROSCI.3970-14.2015. (PMID: 10.1523/JNEUROSCI.3970-14.2015257405206605574) Yoshizaki K, Adachi K, Kataoka S et al (2008) Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice. Exp Neurol 210(2):585–591. https://doi.org/10.1016/j.expneurol.2007.12.005. (PMID: 10.1016/j.expneurol.2007.12.00518222425) Qin Y, Wu J, Chen T, et al (2021) Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations. The J Clin Invest 131(8):e147329, 147329. https://doi.org/10.1172/JCI147329. Liu Y, Kang X, Lin J et al (2024) Myelin endocytosis by brain endothelial cells causes endothelial iron overload and oligodendroglial iron hunger in hypoperfusion-induced white matter injury. CNS Neurosci Ther 30(8):e14925. https://doi.org/10.1111/cns.14925. (PMID: 10.1111/cns.149253916108911333543) Cheng Y, Chen B, Zhang M et al (2025) Carotid endarterectomy ameliorates cognitive impairment in clinical and experimental unilateral carotid artery stenosis. J Am Heart Assoc 14(2):e038388. https://doi.org/10.1161/JAHA.124.038388. (PMID: 10.1161/JAHA.124.0383883981755212054441) Hricisák L, Pál É, Nagy D et al (2024) NO deficiency compromises inter- and intrahemispheric blood flow adaptation to unilateral carotid artery occlusion. Int J Mol Sci 25(2):697. https://doi.org/10.3390/ijms25020697. (PMID: 10.3390/ijms250206973825576910815552) Cui T, Lin J, Zhong M et al (2025) An arteriovenous fistula model: carotid artery-posterior facial vein fistula in rats. J Vasc Access 26(4):1391–1398. https://doi.org/10.1177/11297298241258804. (PMID: 10.1177/1129729824125880439090993) Prim DA, Mohamed MA, Lane BA et al (2018) Comparative mechanics of diverse mammalian carotid arteries. PLoS One 13(8):e0202123. https://doi.org/10.1371/journal.pone.0202123. (PMID: 10.1371/journal.pone.0202123300961856086448) Kakehata J, Togashi H, Yamaguchi T et al (2007) Effects of propofol and halothane on long-term potentiation in the rat hippocampus after transient cerebral ischaemia. Eur J Anaesthesiol 24(12):1021–1027. https://doi.org/10.1017/S0265021507000749. (PMID: 10.1017/S026502150700074917579948) Lu D, Wu Y, Qu Y et al (2016) A modified method to reduce variable outcomes in a rat model of four-vessel arterial occlusion. Neurol Res 38(12):1102–1110. https://doi.org/10.1080/01616412.2016.1249996. (PMID: 10.1080/01616412.2016.124999627796195) Sun W, Chen Y, Zhang Y et al (2021) A modified four vessel occlusion model of global cerebral ischemia in rats. J Neurosci Methods 352:109090. https://doi.org/10.1016/j.jneumeth.2021.109090. (PMID: 10.1016/j.jneumeth.2021.10909033516736) Pereira FM, Ferreira EDF, de Oliveira RMW et al (2012) Time-course of neurodegeneration and memory impairment following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats. Behav Brain Res 229(2):340–348. https://doi.org/10.1016/j.bbr.2012.01.023. (PMID: 10.1016/j.bbr.2012.01.02322274621) Zaghi GGD, Godinho J, Ferreira EDF et al (2016) Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats. Prog Neuropsychopharmacol Biol Psychiatry 65:179–187. https://doi.org/10.1016/j.pnpbp.2015.10.004. (PMID: 10.1016/j.pnpbp.2015.10.00426485403) Romanini CV, Schiavon AP, Ferreira EDF et al (2010) Sildenafil prevents mortality and reduces hippocampal damage after permanent, stepwise, 4-vessel occlusion in rats. Brain Res Bull 81(6):631–640. https://doi.org/10.1016/j.brainresbull.2009.12.012. (PMID: 10.1016/j.brainresbull.2009.12.01220060439) Plaschke K, Bardenheuer HJ, Weigand MA et al (1998) Increased ATP production during long-term brain ischemia in rats in the presence of propentofylline. Eur J Pharmacol 349(1):33–40. https://doi.org/10.1016/s0014-2999(98)00172-1. (PMID: 10.1016/s0014-2999(98)00172-19669493) Zhang X, Liu B, Shao D et al (2026) Anti-inflammatory and neuroprotective effect of bryodulcosigenin against cerebral ischemia/reperfusion injury via modulation of inflammatory signaling pathways. Inflammopharmacology 34(1):525–544. https://doi.org/10.1007/s10787-025-02018-z. (PMID: 10.1007/s10787-025-02018-z41269478) Plaschke K, Ranneberg T, Bauer J et al (1997) The effect of stepwise cerebral hypoperfusion on energy metabolism and amyloid precursor protein (APP) in cerebral cortex and hippocampus in the adult rat. Ann N Y Acad Sci 826:502–506. https://doi.org/10.1111/j.1749-6632.1997.tb48513.x. (PMID: 10.1111/j.1749-6632.1997.tb48513.x9329733) Huang H, Deng X, Wang Y et al (2024) Chronic stress exacerbates cerebral amyloid angiopathy through promoting neutrophil extracellular traps formation. Adv Sci 11(43):e2404096. https://doi.org/10.1002/advs.202404096. (PMID: 10.1002/advs.202404096) Haglund M, Passant U, Sjöbeck M et al (2006) Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia. Int J Geriatr Psychiatry 21(7):681–687. https://doi.org/10.1002/gps.1550. (PMID: 10.1002/gps.155016802283) Vinters HV (2001) Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia? Ann Neurol 49(6):691–693. https://doi.org/10.1002/ana.1055. (PMID: 10.1002/ana.105511409417) Hu M, Li T, Ma X et al (2023) Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model. Nat Commun 14(1):3945. https://doi.org/10.1038/s41467-023-39693-x. (PMID: 10.1038/s41467-023-39693-x3740272110319857) Jury-Garfe N, Chimal-Juárez E, Patel H et al (2025) Tau depletion diminishes vascular amyloid-related deficits in a mouse model of cerebral amyloid angiopathy. Alzheimer’s Dementia 21(5):e70238. https://doi.org/10.1002/alz.70238. (PMID: 10.1002/alz.702384034670612064415) Schelle J, Wegenast-Braun BM, Fritschi SK et al (2019) Early Aβ reduction prevents progression of cerebral amyloid angiopathy. Annal Neurol 86(4):561–571. https://doi.org/10.1002/ana.25562. (PMID: 10.1002/ana.2556231359452) Deinsberger W, Vogel J, Kuschinsky W et al (1996) Experimental intracerebral hemorrhage: description of a double injection model in rats. Neurol Res 18(5):475–477. https://doi.org/10.1080/01616412.1996.11740456. (PMID: 10.1080/01616412.1996.117404568916066) Puy L, Leboullenger C, Auger F et al (2022) Intracerebral hemorrhage-induced cognitive impairment in rats is associated with brain atrophy, hypometabolism, and network dysconnectivity. Front Neurosci 16:882996. https://doi.org/10.3389/fnins.2022.882996. (PMID: 10.3389/fnins.2022.882996358442119280302) Rosenberg GA, Mun-Bryce S, Wesley M et al (1990) Collagenase-induced intracerebral hemorrhage in rats. Stroke 21(5):801–807. https://doi.org/10.1161/01.str.21.5.801. (PMID: 10.1161/01.str.21.5.8012160142) Hartman R, Lekic T, Rojas H et al (2009) Assessing functional outcomes following intracerebral hemorrhage in rats. Brain Res 1280:148–157. https://doi.org/10.1016/j.brainres.2009.05.038. (PMID: 10.1016/j.brainres.2009.05.038194642756918942) Joutel A, Corpechot C, Ducros A et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383(6602):707–710. https://doi.org/10.1038/383707a0. (PMID: 10.1038/383707a08878478) Chabriat H, Joutel A, Dichgans M et al (2009) Cadasil. Lancet Neurol 8(7):643–653. https://doi.org/10.1016/S1474-4422(09)70127-9. (PMID: 10.1016/S1474-4422(09)70127-919539236) Buffon F, Porcher R, Hernandez K et al (2006) Cognitive profile in CADASIL. J Neuro Neuro Psychiatry 77(2):175–180. https://doi.org/10.1136/jnnp.2005.068726. (PMID: 10.1136/jnnp.2005.068726) Dichgans M, Markus HS, Salloway S et al (2008) Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol 7(4):310–318. https://doi.org/10.1016/S1474-4422(08)70046-2. (PMID: 10.1016/S1474-4422(08)70046-218296124) Ruchoux MM, Domenga V, Brulin P et al (2003) Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol 162(1):329–342. https://doi.org/10.1016/S0002-9440(10)63824-2. (PMID: 10.1016/S0002-9440(10)63824-2125079161851116) Joutel A, Monet-Leprêtre M, Gosele C et al (2010) Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest 120(2):433–445. https://doi.org/10.1172/JCI39733. (PMID: 10.1172/JCI39733200717732810078) Cognat E, Cleophax S, Domenga-Denier V et al (2014) Early white matter changes in CADASIL: evidence of segmental intramyelinic oedema in a pre-clinical mouse model. Acta Neuropathol Commun 2:49. https://doi.org/10.1186/2051-5960-2-49. (PMID: 10.1186/2051-5960-2-49248869074035092) Rutten JW, Klever RR, Hegeman IM et al (2015) The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation. Acta Neuropathol Commun 3:89. https://doi.org/10.1186/s40478-015-0268-1. (PMID: 10.1186/s40478-015-0268-1267150874696336) Monet-Leprêtre M, Bardot B, Lemaire B et al (2009) Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain 132(Pt 6):1601–1612. https://doi.org/10.1093/brain/awp049. (PMID: 10.1093/brain/awp049192932352685919) Arboleda-Velasquez JF, Manent J, Lee JH et al (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A 108(21):E128-135. https://doi.org/10.1073/pnas.1101964108. (PMID: 10.1073/pnas.1101964108215555903102344) Kaffashian S, Soumaré A, Zhu YC et al (2016) Long-term clinical impact of vascular brain lesions on magnetic resonance imaging in older adults in the population. Stroke 47(11):2865–2869. https://doi.org/10.1161/STROKEAHA.116.014695. (PMID: 10.1161/STROKEAHA.116.01469527659853) Ninomiya T, Kiyohara Y (2011) [Hypertension and dementia]. Nihon Rinsho. Japanese J Clin Med 69(11):2064-2070. https://europepmc.org/article/MED/22111331. Tzourio C, Anderson C, Chapman N et al (2003) Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Inter Med 163(9):1069–1075. https://doi.org/10.1001/archinte.163.9.1069. (PMID: 10.1001/archinte.163.9.1069) Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293. https://doi.org/10.1253/jcj.27.282. (PMID: 10.1253/jcj.27.28213939773) Tayebati SK, Tomassoni D, Amenta F (2012) Spontaneously hypertensive rat as a model of vascular brain disorder: microanatomy, neurochemistry and behavior. J Neurol Sci 322(1–2):241–249. https://doi.org/10.1016/j.jns.2012.05.047. (PMID: 10.1016/j.jns.2012.05.04722726353) Sabbatini M, Catalani A, Consoli C et al (2002) The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? Mech Ageing Dev. https://doi.org/10.1016/s0047-6374(01)00362-1. (PMID: 10.1016/s0047-6374(01)00362-111796140) Gannon O, Tremble SM, McGinn C et al (2023) Angiotensin II-mediated hippocampal hypoperfusion and vascular dysfunction contribute to vascular cognitive impairment in aged hypertensive rats. Alzheimer’s Dementia 20(2):890–903. https://doi.org/10.1002/alz.13491. (PMID: 10.1002/alz.134913781737610917018) Okamoto K, Yamamoto K, Morita N, et al. (1986). Establishment and use of the M strain of stroke-prone spontaneously hypertensive rat. Journal of Hypertension. Supplement: Official Journal of the International Society of Hypertension. 4(3):S21-24. https://pubmed.ncbi.nlm.nih.gov/3465899/. Omote Y, Deguchi K, Tian F et al (2012) Clinical and pathological improvement in stroke-prone spontaneous hypertensive rats related to the pleiotropic effect of cilostazol. Stroke 43(6):1639–1646. https://doi.org/10.1161/STROKEAHA.111.643098. (PMID: 10.1161/STROKEAHA.111.64309822492522) Goldblatt H, Lynch J, Hanzal RF, et al. (1934). Studies on experimental hypertension: i. the production of persistent elevation of systolic blood pressure by means of renal ischemia. The J Exp Med 59(3):347-379. https://doi.org/10.1084/jem.59.3.347. Shih YH, Tsai SF, Huang SH et al (2016) Hypertension impairs hippocampus-related adult neurogenesis, CA1 neuron dendritic arborization and long-term memory. Neuroscience 322:346–357. https://doi.org/10.1016/j.neuroscience.2016.02.045. (PMID: 10.1016/j.neuroscience.2016.02.04526921651) Ward R, Li W, Abdul Y et al (2019) NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia. Pharmacol Res 142:237–250. https://doi.org/10.1016/j.phrs.2019.01.035. (PMID: 10.1016/j.phrs.2019.01.035308180456486792) Liu H, Zang C, Shang J et al (2022) Gardenia jasminoides J. Ellis extract GJ-4 attenuates hyperlipidemic vascular dementia in rats via regulating PPAR-γ-mediated microglial polarization. Food Nutr Res 19:66. https://doi.org/10.29219/fnr.v66.8101. (PMID: 10.29219/fnr.v66.8101) Tomassoni D, Martinelli I, Moruzzi M et al (2020) Obesity and age-related changes in the brain of the Zucker Lepr fa/fa Rats. Nutrients 12(5):1356. https://doi.org/10.3390/nu12051356. (PMID: 10.3390/nu12051356323975427284640) Martinelli I, Tomassoni D, Roy P et al (2021) Altered brain cholinergic and synaptic markers in obese Zucker Rats. Cells 10(10):2528. https://doi.org/10.3390/cells10102528. (PMID: 10.3390/cells10102528346855078534069) Ye T, Meng X, Wang R et al (2018) Gastrodin Alleviates Cognitive Dysfunction and Depressive-Like Behaviors by Inhibiting ER Stress and NLRP3 Inflammasome Activation in db/db Mice. International J Mol Sci 19(12):3977. https://doi.org/10.3390/ijms19123977. (PMID: 10.3390/ijms19123977) Zhang SY, Ji SX, Bai XM et al (2019) L-3-n-butylphthalide attenuates cognitive deficits in db/db diabetic mice. Metab Brain Dis 34(1):309–318. https://doi.org/10.1007/s11011-018-0356-6. (PMID: 10.1007/s11011-018-0356-630506335) Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365(9468):1415–1428. https://doi.org/10.1016/S0140-6736(05)66378-7. (PMID: 10.1016/S0140-6736(05)66378-715836891) Lee JY, Han K, Kim J et al (2025) Association between metabolic syndrome and young-onset dementia: a nationwide population-based study. Neurology 104(10):e213599. https://doi.org/10.1212/WNL.0000000000213599. (PMID: 10.1212/WNL.000000000021359940267374) Zuo Q, Song L, Gao X et al (2024) Associations of metabolic syndrome with cognitive function and dementia risk: evidence from the UK Biobank cohort. Diabetes Obes Metab 26(12):6023–6033. https://doi.org/10.1111/dom.15977. (PMID: 10.1111/dom.1597739360436) Atti AR, Valente S, Iodice A et al (2019) Metabolic Syndrome, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Longitudinal Studies. The Am J Geriatric Psychiatry: Off J Am Assoc Geriatric Psychiatry 27(6):625–637. https://doi.org/10.1016/j.jagp.2019.01.214. (PMID: 10.1016/j.jagp.2019.01.214) Borshchev YY, Uspensky YP, Galagudza MM (2019) Pathogenetic pathways of cognitive dysfunction and dementia in metabolic syndrome. Life Sci 237:116932. https://doi.org/10.1016/j.lfs.2019.116932. (PMID: 10.1016/j.lfs.2019.11693231606384) Zouridis S, Nasir AB, Aspichueta P et al (2025) The link between metabolic syndrome and the brain. Digestion 106(3):203–211. https://doi.org/10.1159/000541696. (PMID: 10.1159/00054169639369701) Ricci G, Pirillo I, Tomassoni D et al (2017) Metabolic syndrome, hypertension, and nervous system injury: epidemiological correlates. Clin Exp Hypertens 39(1):8–16. https://doi.org/10.1080/10641963.2016.1210629. (PMID: 10.1080/10641963.2016.121062928071980) Bell RD, Winkler EA, Singh I et al (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516. https://doi.org/10.1038/nature11087. (PMID: 10.1038/nature11087226225804047116) Serrano-Pozo A, Das S, Hyman BT (2021) APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 20(1):68–80. https://doi.org/10.1016/S1474-4422(20)30412-9. (PMID: 10.1016/S1474-4422(20)30412-9333404858096522) Sun M, He Q, Sun N et al (2024) Intrinsic capacity, polygenic risk score, APOE genotype, and risk of dementia: a prospective cohort study based on the UK Biobank. Neurology 102(12):e209452. https://doi.org/10.1212/WNL.0000000000209452. (PMID: 10.1212/WNL.000000000020945238843484) Liu X, Li L, Liu F et al (2012) ApoE gene polymorphism and vascular dementia in Chinese population: a meta-analysis. J Neural Transm 119(3):387–394. https://doi.org/10.1007/s00702-011-0714-6. (PMID: 10.1007/s00702-011-0714-621984189) Stocker H, Perna L, Weigl K et al (2021) Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years. Mol Psychiatry 26(10):5812–5822. https://doi.org/10.1038/s41380-020-0764-y. (PMID: 10.1038/s41380-020-0764-y32404947) Ma H, Zhou T, Li X et al (2022) Use of fish oil supplements is differently related to incidence of all-cause and vascular dementia among people with the distinct APOE ε4 dosage. Clin Nutr 41(3):731–736. https://doi.org/10.1016/j.clnu.2022.01.019. (PMID: 10.1016/j.clnu.2022.01.019351722558897253) Lee ES, Yoon JH, Choi J et al (2017) A mouse model of subcortical vascular dementia reflecting degeneration of cerebral white matter and microcirculation. J Cereb Blood Flow Metab 39(1):44–57. https://doi.org/10.1177/0271678X17736963. (PMID: 10.1177/0271678X17736963290530326311665) Yuan J, Liao YS, Zhang TC et al (2025) Disrupted lipid metabolism aggravates ischemic brain injury: targeting FDFT1 for stroke therapy. Mol Neurobiol 62(11):14227–14244. https://doi.org/10.1007/s12035-025-05217-5. (PMID: 10.1007/s12035-025-05217-54067636812511267) Montagne A, Nikolakopoulou AM, Huuskonen MT et al (2021) APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nature Aging 1(6):506–520. https://doi.org/10.1038/s43587-021-00073-z. (PMID: 10.1038/s43587-021-00073-z352915618920485) Sullivan PM, Mezdour H, Aratani Y et al (1997) Targeted replacement of the mouse apolipoprotein E Gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272(29):17972–80. https://doi.org/10.1074/jbc.272.29.17972. (PMID: 10.1074/jbc.272.29.179729218423) Hayden EY, Huang JM, Charreton M et al (2020) Modeling mixed vascular and Alzheimer’s dementia using focal subcortical ischemic stroke in human ApoE4-TR:5XFAD transgenic mice. Transl Stroke Res 11(5):1064–1076. https://doi.org/10.1007/s12975-020-00786-0. (PMID: 10.1007/s12975-020-00786-03208677910075511) Langa KM, Foster NL, Larson EB (2004) Mixed dementia: emerging concepts and therapeutic implications. JAMA 292(23):2901–2908. https://doi.org/10.1001/jama.292.23.2901. (PMID: 10.1001/jama.292.23.290115598922) Schneider JA, Arvanitakis Z, Bang W et al (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69(24):2197–2204. https://doi.org/10.1212/01.wnl.0000271090.28148.24. (PMID: 10.1212/01.wnl.0000271090.28148.2417568013) Kisler K, Nelson AR, Montagne A et al (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18(7):419–434. https://doi.org/10.1038/nrn.2017.48. (PMID: 10.1038/nrn.2017.48285154345759779) Sweeney MD, Kisler K, Montagne A et al (2018) The role of brain vasculature in neurodegenerative disorders. Nature Neurosci 21(10):1318–1331. https://doi.org/10.1038/s41593-018-0234-x. (PMID: 10.1038/s41593-018-0234-x302502616198802) Zhao Y, Gu JH, Dai CL et al (2014) Chronic cerebral hypoperfusion causes decrease of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in mice. Front Aging Neurosci 6:10. https://doi.org/10.3389/fnagi.2014.00010. (PMID: 10.3389/fnagi.2014.00010245750383918671) Gannon OJ, Robison LS, Salinero AE et al (2022) High-fat diet exacerbates cognitive decline in mouse models of Alzheimer’s disease and mixed dementia in a sex-dependent manner. J Neuroinflammation 19(1):110. https://doi.org/10.1186/s12974-022-02466-2. (PMID: 10.1186/s12974-022-02466-2355689289107741) Sun L, Li C, Liu J et al (2022) Effects of ischemia-hypoperfusion on neuro-vascular units in dual transgenic mice with Alzheimer’s disease. Folia Neuropathol 60(2):237–249. https://doi.org/10.5114/fn.2022.117278. (PMID: 10.5114/fn.2022.11727835950476) Denver P, D’Adamo H, Hu S et al (2019) A novel model of mixed vascular dementia incorporating hypertension in a rat model of Alzheimer’s disease. Front Physiol 10:1269. https://doi.org/10.3389/fphys.2019.01269. (PMID: 10.3389/fphys.2019.01269317087926821690) Wardlaw JM, Smith EE, Biessels GJ et al (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12(8):822–838. https://doi.org/10.1016/S1474-4422(13)70124-8. (PMID: 10.1016/S1474-4422(13)70124-8238672003714437) Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9(7):689–701. https://doi.org/10.1016/S1474-4422(10)70104-6. (PMID: 10.1016/S1474-4422(10)70104-620610345) Barisano G, Montagne A, Kisler K et al (2022) Blood-brain barrier link to human cognitive impairment and Alzheimer’s disease. Nat Cardiovasc Res 1(2):108–115. https://doi.org/10.1038/s44161-021-00014-4. (PMID: 10.1038/s44161-021-00014-4354501179017393) Gulej R, Patai R, Ungvari A et al (2025) Impacts of systemic milieu on cerebrovascular and brain aging: insights from heterochronic parabiosis, blood exchange, and plasma transfer experiments. GeroScience 47(5):6207–6376. https://doi.org/10.1007/s11357-025-01657-y. (PMID: 10.1007/s11357-025-01657-y4040797512635022) Lin E, Kamel H, Gupta A et al (2022) Incomplete circle of Willis variants and stroke outcome. Eur J Radiol 153:110383. https://doi.org/10.1016/j.ejrad.2022.110383. (PMID: 10.1016/j.ejrad.2022.110383356614599948548) Mota B, Dos Santos SE, Ventura-Antunes L, et al (2019) White matter volume and white/gray matter ratio in mammalian species as a consequence of the universal scaling of cortical folding.In: Proceedings of the National Academy of Sciences of the United States of America. 116(30):15253-15261. https://doi.org/10.1073/pnas.1716956116. Nieman BJ, de Guzman AE, Gazdzinski LM et al (2015) White and gray matter abnormalities after cranial radiation in children and mice. Int J Radiat Oncol Biol Phys 93(4):882–891. https://doi.org/10.1016/j.ijrobp.2015.07.2293. (PMID: 10.1016/j.ijrobp.2015.07.229326530758) Liu Q, Radwanski R, Babadjouni R et al (2019) Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab 39(2):240–250. https://doi.org/10.1177/0271678X17743670. (PMID: 10.1177/0271678X1774367029192539) Washida K, Hattori Y, Ihara M (2019) Animal models of chronic cerebral hypoperfusion: from mouse to primate. Int J Mol Sci 20(24):6176. https://doi.org/10.3390/ijms20246176. (PMID: 10.3390/ijms20246176318178646941004) Sandarage RV, Galuta A, Tsai EC (2023) P.145 Uncovering differences in oligodendrogenesis between human and rodent spinal cord stem cells. Can J Neurol Sci 50(s2):S96–S96. https://doi.org/10.1017/cjn.2023.233. (PMID: 10.1017/cjn.2023.233) Cai M, Zhang W, Weng Z et al (2017) Promoting neurovascular recovery in aged mice after ischemic stroke - prophylactic effect of omega-3 polyunsaturated fatty acids. Aging Dis 8(5):531–545. https://doi.org/10.14336/AD.2017.0520. (PMID: 10.14336/AD.2017.0520289667995614319) Shaw K, Bell L, Boyd K et al (2021) Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences. Nat Commun 12(1):3190. https://doi.org/10.1038/s41467-021-23508-y. (PMID: 10.1038/s41467-021-23508-y340454658160329) Sabogal-Guáqueta AM, Marmolejo-Garza A, Trombetta-Lima M et al (2023) Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction. Nat Commun 14(1):6454. https://doi.org/10.1038/s41467-023-42096-7. (PMID: 10.1038/s41467-023-42096-73783329210575978) Clarke HA, Ma X, Shedlock CJ et al (2025) Spatial mapping of the brain metabolome lipidome and glycome. Nat Commun 16(1):4373. https://doi.org/10.1038/s41467-025-59487-7. (PMID: 10.1038/s41467-025-59487-74035541012069719) Vaishnavi SN, Vlassenko AG, Rundle MM et al (2010) Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A 107(41):17757–17762. https://doi.org/10.1073/pnas.1010459107. (PMID: 10.1073/pnas.1010459107208375362955101) Tiwari V, Ambadipudi S, Patel AB (2013) Glutamatergic and GABAergic TCA cycle and neurotransmitter cycling fluxes in different regions of mouse brain. J Cerebral Blood Flow Metab 33(10):1523–1531. https://doi.org/10.1038/jcbfm.2013.114. (PMID: 10.1038/jcbfm.2013.114) Tan H, Fu X, Yang R, et al (2025) Dual targeting of FSP1 and xCT: Potential mechanism of anthocyanins in alleviating neuronal ferroptosis in vascular dementia. Phytomed: Int J Phyto Phytopharmacol 142:156608. https://doi.org/10.1016/j.phymed.2025.156608. Fenton-Navarro B, Garduño Ríos D, Torner L et al (2021) Melatonin decreases circulating levels of galectin-3 and cytokines, motor activity, and anxiety following acute global cerebral ischemia in male rats. Arch Med Res 52(5):505–513. https://doi.org/10.1016/j.arcmed.2021.01.009. (PMID: 10.1016/j.arcmed.2021.01.00933563490) Haider S, Tabassum S (2018) Impact of 1-day and 4-day MWM training techniques on oxidative and neurochemical profile in rat brain: a comparative study on learning and memory functions. Neurobiol Learn Mem 155:390–402. https://doi.org/10.1016/j.nlm.2018.09.003. (PMID: 10.1016/j.nlm.2018.09.00330195048) Fuchs E, Flügge G (1998) Stress, glucocorticoids and structural plasticity of the hippocampus. Neurosci Biobehav Rev 23(2):295–300. https://doi.org/10.1016/s0149-7634(98)00031-1. (PMID: 10.1016/s0149-7634(98)00031-19884123) Percie Du Sert N, Hurst V, Ahluwalia A et al (2020) The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol 18(7):e3000410. https://doi.org/10.1371/journal.pbio.3000410. (PMID: 10.1371/journal.pbio.3000410326632197360023) Sriram S, Root K, Chacko K et al (2022) Surgical management of synucleinopathies. Biomedicines 10(10):2657. https://doi.org/10.3390/biomedicines10102657. (PMID: 10.3390/biomedicines10102657362899209599076) Gorelick PB, Scuteri A, Black SE et al (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 42(9):2672–2713. https://doi.org/10.1161/STR.0b013e3182299496. (PMID: 10.1161/STR.0b013e3182299496217784383778669) Soria G, Tudela R, Márquez-Martín A et al (2013) The ins and outs of the BCCAo model for chronic hypoperfusion: a multimodal and longitudinal MRI approach. PLoS One 8(9):e74631. https://doi.org/10.1371/journal.pone.0074631. (PMID: 10.1371/journal.pone.0074631240586093776744) Cox MF, Roberts JM, Shahidehpour RK et al (2026) Temporal evolution of brain inflammation in the bilateral common carotid artery stenosis model of chronic cerebral hypoperfusion. J Inflamm Res. https://doi.org/10.2147/JIR.S574221. (PMID: 10.2147/JIR.S5742214173724412927764) Wan L, Cheng Y, Luo Z et al (2015) Neuroprotection, learning and memory improvement of a standardized extract from Renshen Shouwu against neuronal injury and vascular dementia in rats with brain ischemia. J Ethnopharmacol 165:118–126. https://doi.org/10.1016/j.jep.2015.02.027. (PMID: 10.1016/j.jep.2015.02.02725704930) Mao M, Xu Y, Zhang XY et al (2020) MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling. J Neuro 17(1):244. Gao Y, Tang H, Nie K et al (2019) Hippocampal damage and white matter lesions contribute to cognitive impairment in MPTP-lesioned mice with chronic cerebral hypoperfusion. Behav Brain Res 368:111885. https://doi.org/10.1016/j.bbr.2019.03.054. (PMID: 10.1016/j.bbr.2019.03.05430959125) Godinho J, de Sa-Nakanishi AB, Moreira LS et al (2018) Ethyl-acetate fraction of Trichilia catigua protects against oxidative stress and neuroinflammation after cerebral ischemia/reperfusion. J Ethnopharmacol 221:109–118. https://doi.org/10.1016/j.jep.2018.04.018. (PMID: 10.1016/j.jep.2018.04.01829660468) de la Tremblaye PB, Benoit SM, Schock S et al (2017) CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery. Prog Neuropsychopharmacol Biol Psychiatry 79(Pt B):234–248. https://doi.org/10.1016/j.pnpbp.2017.06.021. (PMID: 10.1016/j.pnpbp.2017.06.02128647536) Che P, Zhang J, Yu M et al (2023) Dl-3-n-butylphthalide promotes synaptic plasticity by activating the Akt/ERK signaling pathway and reduces the blood–brain barrier leakage by inhibiting the HIF-1α/MMP signaling pathway in vascular dementia model mice. CNS Neurosci Ther 29(5):1392–1404. https://doi.org/10.1111/cns.14112. (PMID: 10.1111/cns.141123675670910068471) Toyama K, Spin JM, Deng AC et al (2018) MicroRNA-mediated therapy modulating blood–brain barrier disruption improves vascular cognitive impairment. Arterioscler Thromb Vasc Biol 38(6):1392–1406. https://doi.org/10.1161/ATVBAHA.118.310822. (PMID: 10.1161/ATVBAHA.118.31082229650692) Ma S, Jia J, Wu L et al (2025) Total flavonoids of Dracocephalum moldavica L. alleviate cognitive impairment via TNF-α/NF-κB p65 signaling pathway in vascular dementia rats. Front Pharmacol 16:1640272. https://doi.org/10.3389/fphar.2025.1640272. (PMID: 10.3389/fphar.2025.16402724084336712364899) Tang H, Li Y, Pu Y et al (2026) Investigating the therapeutic mechanism of Puerarin in vascular dementia: an integrated approach combining network pharmacology and experimental validation. Front Pharmacol 17:1796295. https://doi.org/10.3389/fphar.2026.1796295. (PMID: 10.3389/fphar.2026.17962954213733913168132) Hoyer-Kimura C, Hay M, Konhilas JP, et al (2024) PNA5, A novel mas receptor agonist, improves neurovascular and blood-brain-barrier function in a mouse model of vascular cognitive impairment and dementia. Aging Dis 15(4):1927-1951. https://doi.org/10.14336/AD.2023.0928. Sun R, Chen C, Fu Z et al (2026) Qizhi Tongluo capsule improves vascular dementia in rats via integrated metabolomics and molecular mechanism research. J Ethnopharmacol 356:120787. https://doi.org/10.1016/j.jep.2025.120787. (PMID: 10.1016/j.jep.2025.12078741167571) Wang L, Tang C, Lai X (2004) Effects of electroacupuncture on learning, memory and formation system of free radicals in brain tissues of vascular dementia model rats. Journal of Traditional Chinese Medicine = Chung I Tsa Chih Ying Wen Pan 24(2):140-143. https://pubmed.ncbi.nlm.nih.gov/15270273/. Wu Y, Ren Y, Cao L et al (2025) Regulation of mitochondrial autophagy via the PINK1/Parkin pathway to improve cognitive function in vascular dementia using governor vessel acupuncture. Int Immunopharmacol 164:115398. https://doi.org/10.1016/j.intimp.2025.115398. (PMID: 10.1016/j.intimp.2025.11539840848482) Sriram S, Mehkri Y, Quintin S et al (2022) Shared pathophysiology: understanding stroke and Alzheimer’s disease. Clin Neurol Neurosurg 218:107306. https://doi.org/10.1016/j.clineuro.2022.107306. (PMID: 10.1016/j.clineuro.2022.10730635636382) Zhang D, Ruan J, Peng S et al (2024) Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling. Nat Neurosci 27(2):232–248. https://doi.org/10.1038/s41593-023-01515-0. (PMID: 10.1038/s41593-023-01515-03816893210849963) Schneider JA, Arvanitakis Z, Bang W et al (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69(24):2197–2204. (PMID: 10.1212/01.wnl.0000271090.28148.2417568013) Kalaria RN (1996) Cerebral vessels in ageing and Alzheimer’s disease. Pharmacol Ther 72(3):193–214. https://doi.org/10.1016/s0163-7258(96)00116-7. (PMID: 10.1016/s0163-7258(96)00116-79364575) Edgerton-Fulton M, Ergul A (2022) Vascular contributions to cognitive impairment/dementia in diabetes: role of endothelial cells and pericytes. Am J Physiol Cell Physiol 323(4):C1177–C1189. https://doi.org/10.1152/ajpcell.00072.2022. (PMID: 10.1152/ajpcell.00072.2022360364459576164) Goulay R, Flament J, Gauberti M et al (2017) Subarachnoid hemorrhage severely impairs brain parenchymal cerebrospinal fluid circulation in nonhuman primate. Stroke 48(8):2301–2305. https://doi.org/10.1161/STROKEAHA.117.017014. (PMID: 10.1161/STROKEAHA.117.01701428526764) Ding J, Sigurðsson S, Jónsson PV et al (2017) Large perivascular spaces visible on magnetic resonance imaging, cerebral small vessel disease progression, and risk of dementia: the age gene/environment susceptibility-Reykjavik study. JAMA Neurol 74(9):1105–1112. https://doi.org/10.1001/jamaneurol.2017.1397. (PMID: 10.1001/jamaneurol.2017.1397287155525695230) Zhang J, Zhao H, Xue Y et al (2022) Impaired glymphatic transport kinetics following induced acute ischemic brain edema in a mouse pMCAO model. Front Neurol 13:860255. https://doi.org/10.3389/fneur.2022.860255. (PMID: 10.3389/fneur.2022.860255353709108970176) Chen S, Wang H, Zhang L et al (2025) Glymphatic system: a self-purification circulation in brain. Front Cell Neurosci 19:1528995. https://doi.org/10.3389/fncel.2025.1528995. (PMID: 10.3389/fncel.2025.15289954001256711861344) Van Hove H, De Feo D, Greter M et al (2025) Central nervous system macrophages in health and disease. Annu Rev Immunol 43(1):589–613. https://doi.org/10.1146/annurev-immunol-082423-041334. (PMID: 10.1146/annurev-immunol-082423-04133440036702) Li C, Li T, Hu M et al (2025) Novel perivascular macrophage mechanism to promote glymphatic Aβ clearance after stroke. Stroke 56(9):2695–2706. https://doi.org/10.1161/STROKEAHA.124.050266. (PMID: 10.1161/STROKEAHA.124.05026640391473) Vara-Pérez M, Movahedi K (2025) Border-associated macrophages as gatekeepers of brain homeostasis and immunity. Immunity 58(5):1085–1100. https://doi.org/10.1016/j.immuni.2025.04.005. (PMID: 10.1016/j.immuni.2025.04.0054032438112094687) Xu M, Pirtskhalava T, Farr JN et al (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24(8):1246–1256. https://doi.org/10.1038/s41591-018-0092-9. (PMID: 10.1038/s41591-018-0092-9299881306082705)
Contributed Indexing:	Keywords: Animal model; Research review; Vascular dementia
Entry Date(s):	Date Created: 20260730 Date Completed: 20260730 Latest Revision: 20260730
Update Code:	20260730
DOI:	10.1007/s11033-026-12401-w
PMID:	42530688
Βάση Δεδομένων:	MEDLINE

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ISSN:	1573-4978
DOI:	10.1007/s11033-026-12401-w