Alterations in the Blood–Brain Barrier in Mood Disorders and Neurodegenerative Diseases

Abstract

Depressive disorders and suicidal behaviors represent major causes of health loss. Modifications of brain microvasculature, and specifically alterations of the blood–brain barrier have been supposed to participate in the vulnerability to those disorders along with cognitive impairment, especially in the older adults. In this article, we addressed evidence linking blood–brain barrier impairments with mood disorders and suicide. Secondly, we investigated their relationship with depression in old age, and with neurodegenerative processes. Particular attention was drawn toward the potential interactions between the coagulation processes and the blood–brain barrier dysfunctions, as innovative treatment strategies may emerge from research in those fields. Overall, the studies reviewed highlight the implication of multiple dysfunctions of the blood–brain barrier in mood disorders and suicide. Impairments of the blood–brain barrier show relationships with altered expression of endothelial cell junction proteins. These modifications also implicate receptors of the extracellular matrix, the vascular endothelial growth factor, changes in perivascular astrocytes, and has links with local and systemic inflammatory processes. Dysfunctions of the blood–brain barrier underly chronic stress and participate in psychiatric diathesis in old age. In addition, we outline that coagulation processes are likely to interact with the blood–brain barrier and further contribute to neurodegenerative disorders. In conclusion, new pathophysiological models offer perspectives toward detecting new biomarkers in mood disorders and suicide. In parallel, these models open avenues for developing innovative therapeutic agents, although further considering their potential risks and eventual benefits is needed.

Keywords

blood–brain barrier - neuropsychiatry - mood disorders - suicide - depression - coagulation

^* These authors contributed equally to this work.

^** These authors contributed equally to this work.

Publication History

Article published online:
09 March 2025

• References

• 1 Arias-de la Torre J, Vilagut G, Ronaldson A. et al. Prevalence and variability of current depressive disorder in 27 European countries: a population-based study. Lancet Public Health 2021; 6 (10) e729-e738
• 2 WHO. Depressive disorder (depression). 2023. Accessed January 21, 2024 at: https://www.who.int/news-room/fact-sheets/detail/depression
• 3 Hasin DS, Sarvet AL, Meyers JL. et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry 2018; 75 (04) 336-346
• 4 McAllister-Williams RH. When depression is difficult to treat. Eur Neuropsychopharmacol 2022; 56: 89-91
• 5 Rush AJ, Aaronson ST, Demyttenaere K. Difficult-to-treat depression: a clinical and research roadmap for when remission is elusive. Aust N Z J Psychiatry 2019; 53 (02) 109-118
• 6 James SL, Abate D, Abate KH. et al; GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392 (10159): 1789-1858
• 7 Moitra M, Santomauro D, Degenhardt L. et al. Estimating the risk of suicide associated with mental disorders: a systematic review and meta-regression analysis. J Psychiatr Res 2021; 137: 242-249
• 8 De Leo D. Late-life suicide in an aging world. Nat Aging 2022; 2 (01) 7-12
• 9 Naghavi M. Global Burden of Disease Self-Harm Collaborators. Global, regional, and national burden of suicide mortality 1990 to 2016: systematic analysis for the Global Burden of Disease Study 2016. BMJ 2019; 364: l94
• 10 Alexopoulos GS. Mechanisms and treatment of late-life depression. Transl Psychiatry 2019; 9 (01) 188
• 11 Paranthaman R, Greenstein A, Burns AS, Heagerty AM, Malik RA, Baldwin RC. Relationship of endothelial function and atherosclerosis to treatment response in late-life depression. Int J Geriatr Psychiatry 2012; 27 (09) 967-973
• 12 Greene C, Connolly R, Brennan D. et al. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci 2024; 27 (03) 421-432
• 13 Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 2017; 96 (01) 17-42
• 14 Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 2018; 21 (10) 1318-1331
• 15 Chea M, Bouvier S, Gris JC. The hemostatic system in chronic brain diseases: a new challenging frontier?. Thromb Res 2024; 243: 109154
• 16 Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 2016; 19 (06) 771-783
• 17 Liu S, Agalliu D, Yu C, Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des 2012; 18 (25) 3653-3662
• 18 Wang S, Reeves B, Pawlinski R. Astrocyte tissue factor controls CNS hemostasis and autoimmune inflammation. Thromb Res 2016; 141 (Suppl. 02) S65-S67
• 19 Eddleston M, de la Torre JC, Oldstone MB, Loskutoff DJ, Edgington TS, Mackman N. Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis. J Clin Invest 1993; 92 (01) 349-358
• 20 Yao Y, Chen ZL, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun 2014; 5: 3413
• 21 Fisher MJ. Brain regulation of thrombosis and hemostasis: from theory to practice. Stroke 2013; 44 (11) 3275-3285
• 22 Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and sysfunction of the blood-brain barrier. Cell 2015; 163 (05) 1064-1078
• 23 Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008; 57 (02) 178-201
• 24 Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018; 14 (03) 133-150
• 25 Maroney SA, Westrick RJ, Cleuren AC. et al. Tissue factor pathway inhibitor is required for cerebrovascular development in mice. Blood 2021; 137 (02) 258-268
• 26 Ishii H, Salem HH, Bell CE, Laposata EA, Majerus PW. Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain. Blood 1986; 67 (02) 362-365
• 27 Hermann DM, Kleinschnitz C. Thrombomodulin, a master switch controlling poststroke microvascular remodeling and angiogenesis. Arterioscler Thromb Vasc Biol 2020; 40 (12) 2818-2820
• 28 Wong VL, Hofman FM, Ishii H, Fisher M. Regional distribution of thrombomodulin in human brain. Brain Res 1991; 556 (01) 1-5
• 29 Laszik Z, Mitro A, Taylor Jr FB, Ferrell G, Esmon CT. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 1997; 96 (10) 3633-3640
• 30 Gera O, Shavit-Stein E, Bushi D. et al. Thrombin and protein C pathway in peripheral nerve Schwann cells. Neuroscience 2016; 339: 587-598
• 31 Bajaj MS, Kuppuswamy MN, Manepalli AN, Bajaj SP. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues. Thromb Haemost 1999; 82 (03) 1047-1052
• 32 Zetterberg H, Andreasson U, Blennow K. CSF antithrombin III and disruption of the blood-brain barrier. J Clin Oncol 2009; 27 (13) 2302-2303 , author reply 2303–2304
• 33 Xu Y, Slayter HS. Immunocytochemical localization of endogenous anti-thrombin III in the vasculature of rat tissues reveals locations of anticoagulantly active heparan sulfate proteoglycans. J Histochem Cytochem 1994; 42 (10) 1365-1376
• 34 Medcalf RL. Fibrinolysis: from blood to the brain. J Thromb Haemost 2017; 15 (11) 2089-2098
• 35 Brenner B, Gris JC. Coagulation and brain. Semin Thromb Hemost 2013; 39 (08) 847-848
• 36 Gur-Wahnon D, Mizrachi T, Maaravi-Pinto FY. et al. The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention. J Neuroinflammation 2013; 10: 124
• 37 Kim JA, Tran ND, Wang SJ, Fisher MJ. Astrocyte regulation of human brain capillary endothelial fibrinolysis. Thromb Res 2003; 112 (03) 159-165
• 38 Dudek KA, Dion-Albert L, Lebel M. et al. Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression. Proc Natl Acad Sci U S A 2020; 117 (06) 3326-3336
• 39 Dion-Albert L, Cadoret A, Doney E. et al; Signature Consortium. Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue. Nat Commun 2022; 13 (01) 164
• 40 Sun ZW, Wang X, Zhao Y. et al. Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors. Brain Behav Immun 2024; 115: 143-156
• 41 Matsuno H, Tsuchimine S, O'Hashi K. et al. Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression. Mol Psychiatry 2022; 27 (09) 3822-3832
• 42 Gal Z, Torok D, Gonda X. et al. Inflammation and blood-brain barrier in depression: interaction of CLDN5 and IL6 gene variants in stress-induced depression. Int J Neuropsychopharmacol 2023; 26 (03) 189-197
• 43 Wu H, Wang J, Teng T. et al. Biomarkers of intestinal permeability and blood-brain barrier permeability in adolescents with major depressive disorder. J Affect Disord 2023; 323: 659-666
• 44 Maridaki Z, Syrros G, Gianna Delichatsiou S, Warsh J, Konstantinou GN. Claudin-5 and occludin levels in patients with psychiatric disorders—a systematic review. Brain Behav Immun 2025; 123: 865-875
• 45 Xie T, Stathopoulou MG, de Andrés F. et al. VEGF-related polymorphisms identified by GWAS and risk for major depression. Transl Psychiatry 2017; 7 (03) e1055-e1055
• 46 Chen MH, Lin WC, Li CT. et al. Effects of low-dose ketamine infusion on vascular endothelial growth factor and matrix metalloproteinase-9 among patients with treatment-resistant depression and suicidal ideation. J Psychiatr Res 2023; 165: 91-95
• 47 Shang B, Wang T, Zhao S. et al. Higher blood-brain barrier permeability in patients with major depressive disorder identified by DCE-MRI imaging. Psychiatry Res Neuroimaging 2024; 337: 111761
• 48 Kamintsky L, Cairns KA, Veksler R. et al. Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression. Neuroimage Clin 2020; 26: 102049
• 49 Althubaity N, Schubert J, Martins D. et al. Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression. Neuroimage Clin 2022; 33: 102926
• 50 Yun GS, In YN, Kang C. et al. Development of a strategy for assessing blood-brain barrier disruption using serum S100 calcium-binding protein B and neuron-specific enolase in early stage of neuroemergencies: a preliminary study. Medicine (Baltimore) 2022; 101 (28) e29644
• 51 Blyth BJ, Farhavar A, Gee C. et al. Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J Neurotrauma 2009; 26 (09) 1497-1507
• 52 Kroksmark H, Vinberg M. Does S100B have a potential role in affective disorders? A literature review. Nord J Psychiatry 2018; 72 (07) 462-470
• 53 Bartoli F, Misiak B, Crocamo C, Carrà G. Glial and neuronal markers in bipolar disorder: a meta-analysis testing S100B and NSE peripheral blood levels. Prog Neuropsychopharmacol Biol Psychiatry 2020; 101: 109922
• 54 Tural U, Irvin MK, Iosifescu DV. Correlation between S100B and severity of depression in MDD: a meta-analysis. World J Biol Psychiatry 2022; 23 (06) 456-463
• 55 Navinés R, Oriolo G, Horrillo I. et al. High S100B levels predict antidepressant response in patients with major depression even when considering inflammatory and metabolic markers. Int J Neuropsychopharmacol 2022; 25 (06) 468-478
• 56 Wiener CD, Molina ML, Passos M. et al. Neuron-specific enolase levels in drug-naïve young adults with major depressive disorder. Neurosci Lett 2016; 620: 93-96
• 57 Bayard-Burfield L, Alling C, Blennow K, Jönsson S, Träskman-Bendz L. Impairment of the blood-CSF barrier in suicide attempters. Eur Neuropsychopharmacol 1996; 6 (03) 195-199
• 58 Falcone T, Fazio V, Lee C. et al. Serum S100B: a potential biomarker for suicidality in adolescents?. PLoS One 2010; 5 (06) e11089
• 59 Lengvenyte A, Conejero I, Courtet P, Olié E. Biological bases of suicidal behaviours: a narrative review. Eur J Neurosci 2021; 53 (01) 330-351
• 60 Ventorp F, Barzilay R, Erhardt S. et al. The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability. J Affect Disord 2016; 193: 349-354
• 61 Schnieder TP, Trencevska I, Rosoklija G. et al. Microglia of prefrontal white matter in suicide. J Neuropathol Exp Neurol 2014; 73 (09) 880-890
• 62 Schnieder TP, Zhou Qin ID, Trencevska-Ivanovska I. et al. Blood vessels and perivascular phagocytes of prefrontal white and gray matter in suicide. J Neuropathol Exp Neurol 2019; 78 (01) 15-30
• 63 Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun 2014; 42: 50-59
• 64 Mondoloni S, Mameli M, Congiu M. Reward and aversion encoding in the lateral habenula for innate and learned behaviours. Transl Psychiatry 2022; 12 (01) 1-8
• 65 Kim HJ, Yoo H, Kim JY. et al. Postmortem gene expression profiles in the habenulae of suicides: implication of endothelial dysfunction in the neurovascular system. Mol Brain 2022; 15 (01) 48
• 66 Lutz PE, Mechawar N, Turecki G. Neuropathology of suicide: recent findings and future directions. Mol Psychiatry 2017; 22 (10) 1395-1412
• 67 Empana JP, Boutouyrie P, Lemogne C, Jouven X, van Sloten TT. Microvascular contribution to late-onset depression: mechanisms, current evidence, association with other brain diseases, and therapeutic perspectives. Biol Psychiatry 2021; 90 (04) 214-225
• 68 Oh DJ, Bae JB, Kim TH. et al. Association between plasma monocyte trafficking-related molecules and future risk of depression in older adults. J Gerontol A Biol Sci Med Sci 2022; 77 (09) 1803-1809
• 69 Hayley S, Hakim AM, Albert PR. Depression, dementia and immune dysregulation. Brain 2021; 144 (03) 746-760
• 70 Nyúl-Tóth Á, Patai R, Csiszar A. et al. Linking peripheral atherosclerosis to blood-brain barrier disruption: elucidating its role as a manifestation of cerebral small vessel disease in vascular cognitive impairment. Geroscience 2024; 46 (06) 6511-6536
• 71 Montagne A, Nation DA, Sagare AP. et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 2020; 581 (7806): 71-76
• 72 Lv W, Jiang X, Zhang Y. The role of platelets in the blood-brain barrier during brain pathology. Front Cell Neurosci 2024; 17: 1298314
• 73 Li D, Huang LT, Zhang CP, Li Q, Wang JH. Insights into the role of platelet-derived growth factors: implications for Parkinson's disease pathogenesis and treatment. Front Aging Neurosci 2022; 14: 890509
• 74 Bhowmick S, D'Mello V, Caruso D, Wallerstein A, Abdul-Muneer PM. Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury. Exp Neurol 2019; 317: 260-270
• 75 Fang W, Geng X, Deng Y. et al. Platelet activating factor induces blood brain barrier permeability alteration in vitro. J Neuroimmunol 2011; 230 (1-2): 42-47
• 76 Callea L, Arese M, Orlandini A, Bargnani C, Priori A, Bussolino F. Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 1999; 94 (1-2): 212-221
• 77 Hagnelius NO, Boman K, Nilsson TK. Fibrinolysis and von Willebrand factor in Alzheimer's disease and vascular dementia—a case-referent study. Thromb Res 2010; 126 (01) 35-38
• 78 Joly BS, Darmon M, Dekimpe C. et al. Imbalance of von Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than a cause of thrombotic process in critically ill COVID-19 patients. J Thromb Haemost 2021; 19 (09) 2193-2198
• 79 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407 (6801): 258-264
• 80 Iannucci J, Grammas P. Thrombin, a key driver of pathological inflammation in the brain. Cells 2023; 12 (09) 1222
• 81 Iannucci J, Renehan W, Grammas P. Thrombin, a mediator of coagulation, inflammation, and neurotoxicity at the neurovascular interface: implications for Alzheimer's disease. Front Neurosci 2020; 14: 762
• 82 García PS, Ciavatta VT, Fidler JA, Woodbury A, Levy JH, Tyor WR. Concentration-dependent dual role of thrombin in protection of cultured rat cortical neurons. Neurochem Res 2015; 40 (11) 2220-2229
• 83 Grossmann K. Alzheimer's disease—rationales for potential treatment with the thrombin inhibitor dabigatran. Int J Mol Sci 2021; 22 (09) 4805
• 84 Ryu JK, Petersen MA, Murray SG. et al. Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 2015; 6 (01) 8164
• 85 Roy RV, Ardeshirylajimi A, Dinarvand P, Yang L, Rezaie AR. Occupancy of human EPCR by protein C induces β-arrestin-2 biased PAR1 signaling by both APC and thrombin. Blood 2016; 128 (14) 1884-1893
• 86 Zhu D, Wang Y, Singh I. et al. Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor. Blood 2010; 115 (23) 4963-4972
• 87 Prouse T, Majumder S, Majumder R. Functions of TAM receptors and ligands Protein S and Gas6 in atherosclerosis and cardiovascular disease. Int J Mol Sci 2024; 25 (23) 12736
• 88 Melchor JP, Pawlak R, Strickland S. The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J Neurosci 2003; 23 (26) 8867-8871
• 89 Berk M, Mohebbi M, Dean OM. et al. Youth depression alleviation with anti-inflammatory agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin. BMC Med 2020; 18 (01) 16
• 90 Berk M, Woods RL, Nelson MR. et al. Effect of aspirin vs placebo on the prevention of depression in older people: a randomized clinical trial. JAMA Psychiatry 2020; 77 (10) 1012-1020
• 91 Cadogan SL, Powell E, Wing K, Wong AY, Smeeth L, Warren-Gash C. Anticoagulant prescribing for atrial fibrillation and risk of incident dementia. Heart 2021; 107 (23) 1898-1904
• 92 Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 2018; 39 (06) 453-460
• 93 Mongkhon P, Fanning L, Lau WCY. et al. Oral anticoagulant and reduced risk of dementia in patients with atrial fibrillation: a population-based cohort study. Heart Rhythm 2020; 17 (5 Pt A): 706-713
• 94 Cheng W, Liu W, Li B, Li D. Relationship of anticoagulant therapy with cognitive impairment among patients with atrial fibrillation: a meta-analysis and systematic review. J Cardiovasc Pharmacol 2018; 71 (06) 380-387
• 95 Jacobs V, May HT, Bair TL. et al. Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol 2016; 118 (02) 210-214