PDF(1844 KB)
Vascular cognitive impairment and neurovascular inflammaging mechanisms
Sihui WANG, Yan SHEN, Lingjun KONG, Zhengyu LU
Journal of Neurology and Neurorehabilitation ›› 2026, Vol. 22 ›› Issue (2) : 124-133.
PDF(1844 KB)
PDF(1844 KB)
Vascular cognitive impairment and neurovascular inflammaging mechanisms
Vascular cognitive impairment (VCI) is the second most common type of cognitive disorder in the elderly population, ranking only after Alzheimer's disease, with its clinical spectrum encompassing the entire progression from mild cognitive impairment to vascular dementia. Inflammaging, a prevalent low-grade chronic inflammatory state during aging, is closely associated with various age-related diseases, and has been confirmed to play a pivotal role in the occurrence and progression of VCI. The neurovascular unit (NVU), a core structure for maintaining normal brain function, consists of neurons, glial cells, vascular endothelial cells, pericytes, and the basement membrane. Through a complex intercellular signaling network, the NVU collaboratively regulates cerebral blood flow, maintains blood-brain barrier integrity, and provides the metabolic support for neuronal activity. This review focuses on the NVU to systematically elucidate the mechanisms by which inflammaging contributes to the development of VCI, aiming to reveal the intrinsic relationship between inflammaging and VCI from an inflammatory perspective and provide a theoretical basis for a deeper understanding of the pathophysiological processes of VCI.
Vascular cognitive impairment / Inflammaging / Neurovascular unit
| [1] | MOK V C T, CAI Y, MARKUS H S. Vascular cognitive impairment and dementia: Mechanisms, treatment, and future directions[J]. Int J Stroke, 2024, 19(8):838-856. |
| [2] | MARTIN S S, ADAY A W, ALLEN N B, et al. 2025 Heart Disease and Stroke Statistics: A report of US and global data from the American heart association[J/OL]. Circulation, 2025, 151(8):e41-e660[2025-09-25]. . |
| [3] | 中国卒中学会血管性认知障碍分会. 中国血管性认知障碍诊治指南(2024版)[J]. 中华医学杂志, 104(31):2881-2894. |
| [4] | FRANCESCHI C, BONAFè M, VALENSIN S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence[J]. Ann N Y Acad Sci, 2000, 908:244-254. |
| [5] | GORELICK P B. Role of inflammation in cognitive impairment: Results of observational epidemiological studies and clinical trials[J]. Ann N Y Acad Sci, 2010, 1207:155-162. |
| [6] | VOLPATO S, GURALNIK J M, FERRUCCI L, et al. Cardiovascular disease, interleukin-6, and risk of mortality in older women: The women's health and aging study[J]. Circulation, 2001, 103(7):947-953. |
| [7] | DUNCAN B B, SCHMIDT M I, PANKOW J S, et al. Low-grade systemic inflammation and the development of type 2 diabetes: The atherosclerosis risk in communities study[J]. Diabetes, 2003, 52(7):1799-1805. |
| [8] | MUOIO V, PERSSON P B, SENDESKI M M. The neurovascular unit-concept review[J]. Acta Physiol (Oxf), 2014, 210(4):790-798. |
| [9] | MUKLI P, PINTO C B, OWENS C D, et al. Impaired neurovascular coupling and increased functional connectivity in the frontal cortex predict age-related cognitive dysfunction[J/OL]. Adv Sci (Weinh), 2024, 11(10):e2303516[2025-09-25]. . |
| [10] | ADLER A S, SINHA S, KAWAHARA T L, et al. Motif module map reveals enforcement of aging by continual NF-kappaB activity[J]. Genes Dev, 2007, 21(24):3244-3257. |
| [11] | SALMINEN A, HUUSKONEN J, OJALA J, et al. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging[J]. Ageing Res Rev, 2008, 7(2):83-105. |
| [12] | BASISTY N, KALE A, JEON O H, et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development[J/OL]. PLoS Biol, 2020, 18(1):e3000599[2025-09-25]. . |
| [13] | CHEN Y, YANG L. Cellular senescence in renal ischemia-reperfusion injury[J]. Chin Med J (Engl), 2025, 138(15):1794-1806. |
| [14] | LI K, WANG J, CHEN L, et al. Netrin-1 ameliorates postoperative delirium-like behavior in aged mice by suppressing neuroinflammation and restoring impaired blood-brain barrier permeability[J/OL]. Front Mol Neurosci, 2022, 14:751570[2025-09-25]. . |
| [15] | SRINIVAS U S, TAN B W Q, VELLAYAPPAN B A, et al. ROS and the DNA damage response in cancer[J/OL]. Redox Biol, 2019, 25:101084[2025-09-25]. . |
| [16] | MOULTON M J, BARISH S, RALHAN I, et al. Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer's disease-associated genes[J/OL]. Proc Natl Acad Sci U S A, 2021, 118(52):e2112095118[2025-09-25]. . |
| [17] | LIN M M, LIU N, QIN Z H, et al. Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases[J]. Acta Pharmacol Sin, 2022, 43(10):2439-2447. |
| [18] | DERETIC V. A master conductor for aggregate clearance by autophagy[J]. Dev Cell, 2010, 18(5):694-696. |
| [19] | FéSüS L, DEMéNY M, PETROVSKI G. Autophagy shapes inflammation[J]. Antioxid Redox Signal, 2011, 14(11):2233-2243. |
| [20] | HAWKINS B T, DAVIS T P. The blood-brain barrier/neurovascular unit in health and disease[J]. Pharmacol Rev, 2005, 57(2):173-185. |
| [21] | AZARFAR A, CALCINI N, HUANG C, et al. Neural coding: A single neuron's perspective[J]. Neurosci Biobehav Rev, 2018, 94:238-247. |
| [22] | THADATHIL N, NICKLAS E H, MOHAMMED S, et al. Necroptosis increases with age in the brain and contributes to age-related neuroinflammation[J]. Geroscience, 2021, 43(5):2345-2361. |
| [23] | VIVIANI B, BARTESAGHI S, GARDONI F, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases[J]. J Neurosci, 2003, 23(25):8692-8700. |
| [24] | PRIETO G A, TONG L, SMITH E D, et al. TNFα and IL-1β but not IL-18 suppresses hippocampal long-term potentiation directly at the synapse[J]. Neurochem Res, 2019, 44(1):49-60. |
| [25] | TAPELLA L, DEMATTEIS G, RUFFINATTI F A, et al. Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures[J/OL]. Cell Calcium, 2021, 100:102480[2025-09-25]. . |
| [26] | BEZZI P, DOMERCQ M, BRAMBILLA L, et al. CXCR4-activated astrocyte glutamate release via TNFalpha: Amplification by microglia triggers neurotoxicity[J]. Nat Neurosci, 2001, 4(7):702-710. |
| [27] | DING Z, GUO S, LUO L, et al. Emerging roles of microglia in neuro-vascular unit: Implications of microglia-neurons interactions[J/OL]. Front Cell Neurosci, 2021, 15:706025[2025-09-25]. . |
| [28] | MIRZAHOSSEINI G, ADAM J M, NASOOHI S, et al. Lost in translation: Neurotrophins biology and function in the neurovascular unit[J]. Neuroscientist, 2023, 29(6):694-714. |
| [29] | RAPPE A, MCWILLIAMS T G. Mitophagy in the aging nervous system[J/OL]. Front Cell Dev Biol, 2022, 10:978142[2025-09-25]. . |
| [30] | LI W, LI J, LI J, et al. Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice[J/OL]. Science, 2024, 386(6728):eadp6547[2025-09-25]. . |
| [31] | YANG H, ANDERSSON U, BRINES M. Neurons are a primary driver of inflammation via release of HMGB1[J/OL]. Cells, 2021, 10(10):2791[2025-09-25]. . |
| [32] | FUJITA K, MOTOKI K, TAGAWA K, et al. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease[J/OL]. Sci Rep, 2016, 6:31895[2025-09-25]. . |
| [33] | SCHAFER D P, STEVENS B. Microglia function in central nervous system development and plasticity[J/OL]. Cold Spring Harb Perspect Biol, 2015, 7(10):a020545[2025-09-25]. . |
| [34] | QIN L Y, LIU Y X, WANG T G, et al. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia[J]. J Biol Chem, 2004, 279(2):1415-1421. |
| [35] | RAJ D D A, JAARSMA D, HOLTMAN I R, et al. Priming of microglia in a DNA-repair deficient model of accelerated aging[J]. Neurobiol Aging, 2014, 35(9):2147-2160. |
| [36] | SHEA J M, VILLEDA S A. Microglia aging in the hippocampus advances through intermediate states that drive activation and cognitive decline[J/OL]. Elife, 2025, 13:RP97671[2025-09-25]. . |
| [37] | YOUNG A P, DENOVAN-WRIGHT E M. JAK1/2 regulates synergy between interferon gamma and lipopolysaccharides in microglia[J/OL]. J Neuroimmune Pharmacol, 2024, 19(1):14[2025-09-25]. . |
| [38] | GULEN M F, SAMSON N, KELLER A, et al. cGAS-STING drives ageing-related inflammation and neurodegeneration[J]. Nature, 2023, 620(7973):374-380. |
| [39] | WON W, BHALLA M, LEE J H, et al. Astrocytes as key regulators of neural signaling in health and disease[J]. Annu Rev Neurosci, 2025, 48(1):251-276. |
| [40] | SAGGU R, SCHUMACHER T, GERICH F, et al. Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia[J/OL]. Acta Neuropathol Commun, 2016, 4(1):76[2025-09-25]. . |
| [41] | LIDDELOW S A, GUTTENPLAN K A, CLARKE L E, et al. Neurotoxic reactive astrocytes are induced by activated microglia[J]. Nature, 2017, 541(7638):481-487. |
| [42] | ZHANG Y, LIU W, HUANG T, et al. Neuroprotective role of GLT-1/EAAT2 in glutamate-induced excitotoxicity[J/OL]. Behav Brain Res, 2025, 495:115804[2025-09-25]. . |
| [43] | OHNO Y, KUNISAWA N, SHIMIZU S. Emerging roles of astrocyte Kir4.1 channels in the pathogenesis and treatment of brain diseases[J/OL]. Int J Mol Sci, 2021, 22(19):10236[2025-09-25]. . |
| [44] | SPAMPINATO S F, BORTOLOTTO V, CANONICO P L, et al. Astrocyte-derived paracrine signals: Relevance for neurogenic niche regulation and blood-brain barrier integrity[J/OL]. Front Pharmacol, 2019, 10:1346[2025-09-25]. . |
| [45] | MILLS W A, 3RD, WOOAM, JIANGS, et al. Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age[J/OL]. Nat Commun, 2022, 13(1):1794[2025-09-25]. . |
| [46] | HARUWAKA K, IKEGAMI A, TACHIBANA Y, et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation[J/OL]. Nat Commun, 2019, 10(1):5816[2025-09-25]. . |
| [47] | SUGIYAMA S, SASAKI T, TANAKA H, et al. The tight junction protein occludin modulates blood-brain barrier integrity and neurological function after ischemic stroke in mice[J/OL]. Sci Rep, 2023, 13(1):2892[2025-09-25]. . |
| [48] | ELAHY M, JACKAMAN C, MAMO J C, et al. Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment[J/OL]. Immun Ageing, 2015, 12:2[2025-09-25]. . |
| [49] | DIMAIO T A, SHEIBANI N. PECAM-1 isoform-specific functions in PECAM-1-deficient brain microvascular endothelial cells[J]. Microvasc Res, 2008, 75(2):188-201. |
| [50] | XIAO K, ALLISON D F, KOTTKE M D, et al. Mechanisms of VE-cadherin processing and degradation in microvascular endothelial cells[J]. J Biol Chem, 2003, 278(21):19199-19208. |
| [51] | FUJIWARA K. Platelet endothelial cell adhesion molecule-1 and mechanotransduction in vascular endothelial cells[J]. J Intern Med, 2006, 259(4):373-380. |
| [52] | PARK H, SHIN J A, LIM J, et al. Increased Caveolin-2 expression in brain endothelial cells promotes age-related neuroinflammation[J]. Mol Cells, 2022, 45(12):950-962. |
| [53] | O'CARROLL S J, KHO D T, WILTSHIRE R, et al. Pro-inflammatory TNFα and IL-1β differentially regulate the inflammatory phenotype of brain microvascular endothelial cells[J/OL]. J Neuroinflammation, 2015, 12:131[2025-09-25]. . |
| [54] | VAN ASSEMA D M, LUBBERINK M, BOELLAARD R, et al. P-glycoprotein function at the blood-brain barrier: Effects of age and gender[J]. Mol Imaging Biol, 2012, 14(6):771-776. |
| [55] | SWEENEY M D, AYYADURAI S, ZLOKOVIC B V. Pericytes of the neurovascular unit: Key functions and signaling pathways[J]. Nat Neurosci, 2016, 19(6):771-783. |
| [56] | WINKLER E A, SAGARE A P, ZLOKOVIC B V. The pericyte: A forgotten cell type with important implications for Alzheimer's disease?[J]. Brain Pathol, 2014, 24(4):371-386. |
| [57] | DANEMAN R, ZHOU L, KEBEDE A A, et al. Pericytes are required for blood-brain barrier integrity during embryogenesis[J]. Nature, 2010, 468(7323):562-566. |
| [58] | DAVE J M, CHAKRABORTY R, AGYEMANG A, et al. Loss of TGFβ-mediated repression of Angiopoietin-2 in pericytes underlies germinal matrix hemorrhage pathogenesis[J]. Stroke, 2024, 55(9):2340-2352. |
| [59] | FERNáNDEZ-KLETT F, PRILLER J. Diverse functions of pericytes in cerebral blood flow regulation and ischemia[J]. J Cereb Blood Flow Metab, 2015, 35(6):883-887. |
| [60] | NIPPERT A R, BIESECKER K R, NEWMAN E A. Mechanisms mediating functional hyperemia in the brain[J]. Neuroscientist, 2018, 24(1):73-83. |
/
| 〈 |
|
〉 |
