Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disease with no existing treatment leading to full recovery. The blood-brain barrier (BBB) breakdown usually precedes the advent of first symptoms in AD and accompanies the progression of the disease. At the same time deliberate BBB opening may be beneficial for drug delivery in AD. Non-invasive brain stimulation (NIBS) techniques, primarily transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have shown multiple evidence of being able to alleviate symptoms of AD. Currently, TMS/tDCS mechanisms are mostly investigated in terms of their neuronal effects, while their possible non-neuronal effects, including mitigation of the BBB disruption, are less studied. We argue that studies of TMS/tDCS effects on the BBB in AD are necessary to boost the effectiveness of neuromodulation in AD. Moreover, such studies are important considering the safety issues of TMS/tDCS use in the advanced AD stages when the BBB is usually dramatically deteriorated. Here, we elucidate the evidence of NIBS-induced BBB opening and closing in various models from in vitro to humans, and highlight its importance in AD.
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Introduction
Alzheimer’s disease (AD) debilitates a large number of older individuals worldwide, and the affected population is increasing due to greater human longevity, incurring enormous costs on treatment and palliative care1. Usually initial symptoms of AD, such as memory loss and slower response times are recognized only when tremendous changes in the brain have already occurred, that is why the therapeutic strategies usually target highly affected brain2,3. Several pharmacological approaches are currently applied as prospective tools for AD treatment, however, the drug therapy is still far from being highly effective in AD4,5,6,7. Non-Invasive Brain Stimulation (NIBS) techniques have been tested both as an alternative and an addition to pharmacological approaches in AD8,9. In recent years, the number of efforts to shed light on NIBS mechanisms in AD increased substantially (see for the review10). In the majority of these studies, primarily neural mechanisms were targeted. However, AD is characterized not only by the neural mechanisms2,3 but also by non-neuronal changes including the substantial blood-brain barrier (BBB) breakdown11,12. At the same time, there are ongoing clinical trials (https:// clinicaltrials.gov/ [12/21/2022]) aiming at the BBB opening by focused ultrasound stimulation (FUS) for better drug delivery in AD. In AD, the most used NIBS approaches are transcranial magnetic stimulation (TMS) and direct current stimulation (tDCS)10,13, and their effects on the BBB have not been studied extensively yet. We argue that studies of TMS/tDCS effects on the BBB in AD are necessary to better understand their mechanisms and to boost their effectiveness in AD. Moreover, such studies are important considering the safety issues of NIBS use in AD stages when the BBB is damaged. Here, we elucidate the evidence of NIBS-induced BBB changes in humans, animals, and cellular models and highlight its importance in AD.
Blood–brain barrier role in Alzheimer’s disease: etiology, pathophysiology, and modeling
The BBB is a semi-permeable membrane within mature brain microvessels, protecting neurons from factors presenting in the systemic circulation. The BBB is formed by the components of the neurovascular unit—vascular cells (endothelial cells, pericytes, smooth muscle cells), glia (astrocytes, oligodendroglia, microglia), neurons and extracellular matrix11,14,15. Endothelial cells form tight junctions—a physical barrier, whereas other cell types provide signaling among the cells. The BBB breakdown in AD is an increase in vascular permeability associated with a decrease in the expression of tight junction proteins (Fig. 1; ref. 16). The BBB breakdown accompanies even healthy aging, while in patients with mild cognitive impairment and AD dementia, the BBB breakdown is accelerated17. The BBB-associated changes may be an early AD biomarker18,19. Notably, brain endothelial cells, among all vascular cells, demonstrate their higher vulnerability in AD, based on gene expression data20. Although there is no etiotropic treatment, the search for AD biomarkers at early stages is important21 because the early diagnosis may serve as a motivation to correct a lifestyle and decrease possibly modifiable risks. For example, positron emission tomography (PET) studies have already shown that patients with mild cognitive impairment have reduced glucose uptake across the BBB and, therefore, disintegrated BBB in young subjects may be considered an early marker of AD22,23. The BBB leakage is associated with changes in tight junctions, the overall BBB permeability index, transendothelial resistance, etc24,25., and all such alterations were reported in AD pathology (Fig. 1)26,27.
Considering the key role of the BBB in pharmacological brain therapy in general, there are already plenty of approaches allowing to assess the BBB permeability, such as (1) in vitro transwell models, allowing BBB permeability assessment to fluorescent tracers and transendothelial electrical resistance (TEER)28,29,30,31; (2) in vivo techniques like microdialysis, used for the analysis of the BBB permeability changes during or after an intervention (e.g., NIBS, drug, injection of a pathogenic AD-associated protein)32; (3) specific type of positron emission tomography: F-2-fluoro-2-deoxy-d-glucose-PET in humans33,34.
The BBB disruption and Aβ propagation seem to be intertwined, but they are mostly parallel processes. It is known that in AD, matrix metalloproteinases may digest tight junction and adherent proteins of the BBB27, decreasing the levels of tight junction proteins in the brain, and resulting in the physical breakdown of the BBB26. Aβ in AD also alters the tight junction proteins content, destroying the BBB29,35. Recent preliminary data have demonstrated that repetitive TMS (rTMS) simultaneously diminishes the matrix metalloproteases level and improves cognitive functioning in MCI patients36,37. AD-induced BBB abnormalities associated with changes in matrix metalloproteinase (MMP) and tight junction protein content are tightly connected with amyloid, and it makes these parameters sensitive to strong therapeutic stimuli. Brain stimulation is supposed to belong to a number of stimuli that may affect AD progression via the BBB disruption. Better understanding of the pathogenic proteins associated with AD—either peripheral or central—is needed for better understanding of the BBB role in AD. A collaborative work between clinicians and scientists is required to piece together knowledge on AD progression and the BBB breakdown.
Non-invasive brain stimulation as a possible treatment in Alzheimer’s disease
Among techniques most widely used to target neuronal dysfunction in neurodegeneration, TMS and tDCS are in precise focus of the perspective. NIBS-mediated modulation of cognitive functions in AD is commonly considered to be connected with the changes in neural activity13,38, while vascular aspects are mostly overlooked. At the same time, vascular pathology in AD is highly amyloid-dependent considering (1) probable amyloid peripheral origin, (2) its high concentration in the brain blood flow, (3) co-localization of classic and diffuse amyloid plaques with the brain vessels, and (4) known biochemical and functional amyloid effects on the BBB cells29,39,40,41. Thus, NIBS amyloid targeting may be considered in a tight association with probable NIBS effects on the brain vascular system. Among attractive targets for TMS/tDCS application in AD are the frontal lobe, specifically, Broca’s area, dorsolateral prefrontal cortex, parieto-temporal lobe (Wernicke’s area), bilateral parietal somatosensory association cortices, temporal lobe42,43,44,45.
tDCS is a safe and easy-applicable method, which is widely studied in AD. Different tDCS protocols applied in AD patient cohorts improved recognition memory and general cognitive abilities, but the results were variable among studies45,46,47. A randomized, placebo-controlled study in AD patients revealed no effect of temporal cortex tDCS on cognition48, while the studies confirming temporal lobe tDCS effects in AD differed in study design, protocols and cognitive tasks45,49.
TMS is another widely used NIBS approach with better spatial accuracy compared to tDCS. The use of TMS at the earlier stages of AD was demonstrated as a prospective tool for treatment38,50. According to Dong and co-authors’ review42, TMS modulates cognitive functions based on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), but does not affect Mini-Mental State Examination (MMSE) score. The review articulates the importance of TMS frequency in AD treatment: high-frequency rTMS shows big effect, at least based on ADAS-Cog scale. Multiple TMS/tDCS studies both in patients and in healthy participants were followed by their unsuccessful replications51,52,53,54. We hypothesize that replication failures related to TMS/tDCS application in AD may be in part connected with our poor understanding of their non-neuronal effects, including effects on the BBB.
Possible influence of transcranial magnetic and electric stimulation on blood-brain barrier in Alzheimer’s disease
Here, we focus on the BBB as a probable mediator of NIBS effects in AD. The BBB-mediated random NIBS effects may be connected with changes in tight junction protein expression, transendothelial resistance, permeability to molecules, etc. We suggest that in AD, TMS/TES-induced non-neuronal changes may be an important mediator of TMS/TES effects. Apart from the immediate changes of the BBB permeability, there is evidence of the endothelial intracellular parameters’ change, including mitochondria abnormalities and FGF-2-related changes55. Interestingly, magnetic field effects on endothelial cells may be associated with the same factors56,57,58. Electric field effects on endothelial cells are mediated by vascular endothelial growth factor (VEGF) receptor signaling, activation of ATP-receptor P2Y, Ca2+and NO concentration transients59,60,61. These factors are highly involved in AD pathology62,63,64. Importantly, in AD mouse model, BBB endothelial cells produce a variety of factors, such as thrombin, vascular endothelial growth factor (VEGF), angiopoietin-2, tumor necrosis factor (TNF), transforming growth factor, interleukin (IL) IL-1, IL-6, IL-8, monocyte chemoattractant protein-1, hypoxia-inducible factor-1, MMPs, and integrins that may promote AD pathogenesis65. A systematic analysis of NIBS effects on AD-associated factors in endothelial cells has not yet been conducted, but some data regarding neurons and glial cells are already available. It was reported, for example, that 10 Hz rTMS may significantly modulate anti- and proinflammatory marker expression either in primary astrocytes exposed to oxygen-glucose deprivation/ reoxygenation and make a neuroprotective effect66. For instance, the expression of IL-10 gene, associated with anti-inflammation, significantly increased in the astrocyte culture after 10 Hz rTMS66. Thus, as interleukin-10 is a supporting factor for the endothelium67, we hypothesize that NIBS might induce both direct and indirect effects on the endothelial cells, at least within a neurovascular unit. All this legitimates the concerns about the necessity to test the BBB integrity before/after TMS/TES application in AD. As the BBB state and AD progression are connected11,68, we hypothesize that in the earlier stages of AD, TMS/TES is applied to a brain with a less damaged BBB. In contrast, at later stages, TMS/TES influences already a not-integrative BBB (Fig. 1). Thus, for the early AD stages, the possibility of short-term NIBS-induced BBB opening may be helpful for drug delivery, while for the later AD stages, BBB restoration can be considered a goal, and an excessive BBB opening is a safety issue. Here, we discuss the experimental works dedicated to the effects of magnetic (Table 1) and electric (Table 2) stimulation on endothelial cell cultures and the BBB cells, in vivo animal models, and in humans and argue for their relevance for TMS/TES neuromodulation in AD.
NIBS effects on blood-brain barrier opening
NIBS-induced BBB opening may be promising for drug delivery in AD, and it has already been tested for the hippocampus69,70 and prefrontal cortex71 using FUS. At the same time, BBB opening may be a safety concern in AD. Thus, one should test whether TMS/tDCS-induced BBB opening is not associated with pathological features of the BBB deterioration characteristic for AD (e.g. pericyte, endothelial, and neuronal degeneration; the BBB transporter function abnormalities; inflammation; accumulation of toxic agents)11. The TMS/tDCS effects on BBB opening are summarized below. The effect of magnetic stimulation on the BBB-associated mechanisms was investigated from the very beginning of TMS use. In the early 1990 study, Ravnborg and co-authors showed that single-pulse TMS in a rat did not change the BBB permeability72. However, since that time, there were several successful efforts to open the BBB using TMS73,74. TMS increased BBB permeability both in animals (in rats, at a low frequency but not at a high frequency) and in patients with malignant brain tumors73. Recently, in an attempt to trigger the BBB opening in a rat model, repetitive low-frequency TMS was applied to the rat’s right hemisphere, and fluorescent angiography revealed ̴ 18% increased permeability 15 min after the stimulation onset. After the other 15 min, vascularization gets normalized74. It is worth noting that to be effective, NIBS-induced BBB opening interventions should be developed considering the pharmacokinetics, as the peak concentration of a drug in the brain may be achieved only in 2–3 h after the drug administration75. Also, there is significant evidence to support that tDCS may also modulate BBB integrity (see the review76). It was reported that tDCS temporarily increased the BBB permeability in a rat brain, and this effect was mediated by NO61. Nitric oxide synthase (NOS) inhibitor ameliorated tDCS-induced BBB permeability61. To our knowledge, there is the only human study, investigating BBB changes after 1 milliampere (mA) tDCS in healthy participants, which did not reveal any BBB changes using diffusion-weighted MRI77.
NIBS effects on blood–brain barrier closure
Interestingly, there are also data supporting the BBB closing effect of NIBS. For instance, in the recent rTMS work on a rabbit eye model, it was shown that the expression of a tight junction protein ZO-1 increased after repetitive magnetic stimulation78. The main limitation of this study is that stimulation was applied to the cornea of a rabbit keratopathy model and, thus, targeted corneal epithelial barrier functions, not the BBB. However, the corneal epithelial and endothelial tissues in the brain vessels are similar in terms of ZO-1 expression, which may indirectly indicate that TMS might also strengthen the BBB in certain circumstances. Another study using electroconvulsive therapy on the Gunn rat model showed an increase in tight junction protein claudin-5 expression and astrocytic coverage of the brain blood vessels after stimulation79. The limitation of this study is that one may not directly compare electrical, magnetic, and electroconvulsive therapy due to the different principles behind them. In the other recent work on the photothrombotic stroke rat model, the BBB damage was successfully mitigated by theta-burst TMS: BBB-associated tight junction protein expression, morphology, and perfusion of vessels preserved80. However, the direct comparison of the BBB modulation mechanisms in stroke and in AD is challenging, as the BBB disruption may be triggered by different factors81. To our knowledge, there are no studies directly reporting that NIBS in AD will lead to the BBB closure or may hamper the transport of pharmacotherapeutic agents to the brain.
There are also a few studies trying to mitigate the BBB disruption using TMS/TES where no clear effect on the BBB was shown. In vitro, endothelial cells HUVEC showed a change in their morphology and increased in number after exposure to static magnetic fields for 24 h a day; however, no effect was detected after shorter stimulation82. Although HUVEC cell line is not a BBB line, it is successfully used in BBB modeling83. An important marker of the BBB integrity—tight junction proteins expression - was not evaluated, while endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) concentration—other sensitive markers in AD—were analyzed. eNOS expression increased after long-term exposure to the magnetic field, while NO level did not change82. In another study, to model the effect of tDCS on the BBB functions, a direct electrical current was applied to endothelial cells bEnd.384. Anti-ZO-1 immunostaining of the cells demonstrated no damage to the cell monolayer integrity84. Probably, the intracellular parameters (e.g., NO, Ca2+) are more sensitive than physiological parameters (e.g., transendothelial electrical resistance and BBB permeability to fluorescent tracers), however, the last ones are more significant as markers for the assessment of the NIBS effect.
We can conclude that the majority of the NIBS effects on BBB in the non-pathological model were toward BBB opening. In those studies when the BBB integrity was increased, pathological models were used85,86,87.
Discussion
There are many blind spots in AD pathology, which result in difficulties in the formulation of a desirable therapeutic effect of NIBS on the BBB. To answer this question, a translational approach is needed. However, translational studies of NIBS effects on the BBB in AD are challenging because, on the one hand, BBB studies are difficult in humans, and on the other hand, NIBS studies are difficult in in vitro and in vivo models. Lack of understanding of non-neuronal NIBS mechanisms in AD leaves multiple questions unanswered. Should one aim at BBB opening or closing in AD patients depending on the AD stage? Is the BBB state associated with the changes in cognitive performance? Is NIBS-induced BBB opening similar to the mechanism of the BBB disruption in neurodegeneration? Is NIBS effect in AD similar to NIBS effect in other conditions where BBB is compromised, such as multiple sclerosis11,88,89, Diabetes Mellitus90, etc. We believe that more studies should address the question of NIBS effects on the BBB as in AD, as well as in healthy aging. We believe that the parameters of a model should be chosen with an emphasis on its sensitivity to reveal possible fine NIBS effects on the BBB. We summarize candidate parameters for the future BBB investigation in cells, animals, and humans, in Table 3. We argue that in order to extrapolate the results of in vitro and in vivo animal works to human participants, one has to study NIBS effects on key components of AD pathology such as extra- and intracellular ion concentration changes, transendothelial resistance, and the proteins, primarily, Aβ and tau. At the same time, NIBS effects on transendothelial resistance and other in vivo parameters should be probed not only in intact animals but also in AD animal models. Yet another point for the NIBS effects on the BBB in AD is that additional investigation may be needed to assess NIBS-induced BBB mitigation in advanced AD stages for safety reasons. Considering that BBB mitigation using transcranial ultrasound stimulation (TUS) is already performed in clinical studies91,92, we believe that the approaches used for the BBB assessment in such studies may be extrapolated to TMS/TES studies.
Conclusion
NIBS techniques are widely tested as an alternative and an addition to pharmacological therapy in AD8,9,69. In this paper, we draw attention to the probable non-neuronal effects of NIBS such as BBB changes, both its opening and closing, and highlight its importance in AD. On the one hand, the BBB is vulnerable in AD, and its further deterioration might aggravate the pathology. On the other hand, BBB opening may be beneficial in AD in some cases for the purpose of drug delivery. We illustrate our point using evidence from human, animal, and cellular models (Fig. 2). The adaptation of NIBS protocols to re- and de novo investigating its effects on the BBB may be an important direction of the research in the field. We suggest that NIBS effects on the BBB should be investigated more considering that a large pool of cerebral blood vessels is located on the surface of the cortex, and is well accessible for NIBS.
References
2021 Alzheimer’s disease facts and figures. Alzheimers Dement 17, 327–406 (2021).
Mucke, L. Neuroscience: Alzheimer’s disease. Nature 461, 895–897 (2009).
Sengoku, R. Aging and Alzheimer’s disease pathology. Neuropathology 40, 22–29 (2020).
Mehta, D., Jackson, R., Paul, G., Shi, J. & Sabbagh, M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin. Investig. Drugs 26, 735–739 (2017).
Casey, D. A., Antimisiaris, D. & O’Brien, J. Drugs for Alzheimer’s disease: are they effective? P T 35, 208–211 (2010).
Huang, L.-K., Chao, S.-P. & Hu, C.-J. Clinical trials of new drugs for Alzheimer disease. J. Biomed. Sci. 27, 18 (2020).
Becker, R. E., Greig, N. H. & Giacobini, E. Why do so many drugs for Alzheimer’s disease fail in development? Time for new methods and new practices? J. Alzheimers Dis. 15, 303–325 (2008).
Menardi, A. et al. Toward noninvasive brain stimulation 2.0 in Alzheimer’s disease. Ageing Res. Rev. 75, 101555 (2022).
Freitas, C., Mondragón-Llorca, H. & Pascual-Leone, A. Noninvasive brain stimulation in Alzheimer’s disease: systematic review and perspectives for the future. Exp. Gerontol. 46, 611–627 (2011).
Teselink, J. et al. Efficacy of non-invasive brain stimulation on global cognition and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review. Ageing Res. Rev. 72, 101499 (2021).
Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).
Yu, X., Ji, C. & Shao, A. Neurovascular unit dysfunction and neurodegenerative disorders. Front. Neurosci. 14, 334 (2020).
Koch, G. et al. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer’s disease. Neuroimage 169, 302–311 (2018).
Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R. & Begley, D. J. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37, 13–25 (2010).
Chen, C. & Li, P. Neurovascular unit protection—novel therapeutic targets and strategies. CNS Neurosci. Ther. 27, 5–6 (2021).
Yamazaki, Y. et al. Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression. Brain 142, 1077–1092 (2019).
Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).
Nation, D. A. et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).
Hussain, B., Fang, C. & Chang, J. Blood–brain barrier breakdown: an emerging biomarker of cognitive impairment in normal aging and dementia. Front. Neurosci. 15, 688090 (2021).
Yang, A. C. et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603, 885–892 (2022).
Klyucherev, T. O. et al. Advances in the development of new biomarkers for Alzheimer’s disease. Transl. Neurodegener. 11, 25 (2022).
Hunt, A. et al. Reduced cerebral glucose metabolism in patients at risk for Alzheimer’s disease. Psychiatry Res.: Neuroimaging 155, 147–154 (2007).
Mosconi, L. et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s disease, and other dementias. J. Nucl. Med. 49, 390–398 (2008).
Lochhead, J. J., Yang, J., Ronaldson, P. T. & Davis, T. P. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front. Physiol. 11, 914 (2020).
Liu, W., Wang, Z., Zhang, L., Wei, X. & Li, L. Tight junction in blood‐brain barrier: an overview of structure, regulation, and regulator substances. CNS Neurosci. Ther. 18, 609–615 (2012).
Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).
Rempe, R. G., Hartz, A. M. & Bauer, B. Matrix metalloproteinases in the brain and blood–brain barrier: versatile breakers and makers. J. Cereb. Blood Flow. Metab. 36, 1481–1507 (2016).
Wilhelm, I., Fazakas, C. & Krizbai, I. A. In vitro models of the blood-brain barrier. Acta Neurobiol. Exp. 71, 113–128 (2011).
Kook, S.-Y. et al. Aβ1–42-RAGE interaction disrupts tight junctions of the blood–brain barrier via Ca2+-calcineurin signaling. J. Neurosci. 32, 8845–8854 (2012).
Wan, W. et al. Aβ(1-42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins. J. Neurochem. 134, 382–393 (2015).
Petrovskaya A. V. et al. [Blood-Brain Barrier Transwell Modeling]. Mol Biol (Mosk) 56, 1086–1094 (2022).
Nicolazzo, J. A., Charman, S. A. & Charman, W. N. Methods to assess drug permeability across the blood-brain barrier. J. Pharm. Pharm. 58, 281–293 (2006).
Tournier N. et al. Influence of P-Glycoprotein Inhibition or Deficiency at the Blood-Brain Barrier on (18)F-2-Fluoro-2-Deoxy-D-glucose ((18)F-FDG) Brain Kinetics. AAPS J. 17, 652–9 (2015).
Hugon, G. et al. [18F]2-fluoro-2-deoxy-sorbitol PET imaging for quantitative monitoring of enhanced blood-brain barrier permeability induced by focused ultrasound. Pharmaceutics 13, 1752 (2021).
Marco, S. & Skaper, S. D. Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells. Neurosci. Lett. 401, 219–224 (2006).
Cirillo, G. et al. Long-Term Neuromodulatory Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Plasmatic Matrix Metalloproteinases (MMPs) Levels and Visuospatial Abilities in Mild Cognitive Impairment (MCI). Int. J. Mol. Sci. 24, 3231 (2023).
Cirillo, G., Pepe, R., Esposito, S., Trojsi, F. & Papa, M. Effects of repetitive transcranial magnetic stimulation (rTMS) on matrix metalloproteases levels and cognitive measures in MCI patients. IJAE 126, 173 (2022).
Zhao, J. et al. Repetitive transcranial magnetic stimulation improves cognitive function of Alzheimer’s disease patients. Oncotarget 8, 33864–33871 (2017).
Cuevas, E. et al. Amyloid Beta 25-35 induces blood-brain barrier disruption in vitro. Metab. Brain Dis. 34, 1365–1374 (2019).
Petrovskaya, A. V. et al. Distinct effects of beta-amyloid, its isomerized and phosphorylated forms on the redox status and mitochondrial functioning of the blood–brain barrier endothelium. Int. J. Mol. Sci. 24, 183 (2023).
Armstrong, R. A. Beta-amyloid plaques: stages in life history or independent origin? Dement Geriatr. Cogn. Disord. 9, 227–238 (1998).
Dong, X. et al. Repetitive transcranial magnetic stimulation for the treatment of Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. PLoS One 13, e0205704 (2018).
Bentwich, J. et al. Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a proof of concept study. J. Neural Transm. (Vienna) 118, 463–471 (2011).
Saxena, V. & Pal, A. Role of Transcranial Direct Current Stimulation in the Management of Alzheimer’s Disease: A Meta-analysis of Effects, Adherence and Adverse Effects. Clin Psychopharmacol Neurosci Off Sci J Korean Coll Neuropsychopharmacol 19, 589–599 (2021).
Boggio, P. S. et al. Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease. J. Neurol. Neurosurg. Psychiatry 80, 444–447 (2008).
Ferrucci, R. et al. Transcranial direct current stimulation improves recognition memory in Alzheimer disease. Neurology 71, 493–498 (2008).
Chang, C.-H., Lane, H.-Y. & Lin, C.-H. Brain stimulation in Alzheimer’s disease. Front. Psychiatry 9, 201 (2018).
Bystad, M. et al. Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer’s disease: a randomized, placebo-controlled trial. Alzheimers Res. Ther. 8, 13 (2016).
Bystad, M., Rasmussen, I. D., Grønli, O. & Aslaksen, P. M. Can 8 months of daily tDCS application slow the cognitive decline in Alzheimer’s disease? A case study. Neurocase 23, 146–148 (2017).
Rutherford, G., Lithgow, B. & Moussavi, Z. Short and long-term effects of rTMS treatment on Alzheimer’s disease at different stages: a pilot study. J. Exp. Neurosci. 9, 43–51 (2015).
Jonker, Z. D. et al. No effect of anodal tDCS on motor cortical excitability and no evidence for responders in a large double-blind placebo-controlled trial. Brain Stimul. 14, 100–109 (2021).
Vannorsdall, T. D. et al. Reproducibility of tDCS results in a randomized trial: failure to replicate findings of tDCS-induced enhancement of verbal fluency. Cogn. Behav. Neurol. 29, 11–17 (2016).
Petrovskaya, A. et al. Examining the effects of transcranial direct current stimulation on human episodic memory with machine learning. PLoS ONE 15, e0235179 (2020).
Ovadia-Caro, S. et al. Predicting the response to non-invasive brain stimulation in stroke. Front. Neurol. 10, 302 (2019).
Parodi-Rullán, R., Sone, J. Y. & Fossati, S. Endothelial mitochondrial dysfunction in cerebral amyloid angiopathy and Alzheimer’s disease. J. Alzheimers Dis. 72, 1019–1039 (2019).
Potenza, L. et al. Effects of a 300 mT static magnetic field on human umbilical vein endothelial cells. Bioelectromagnetics 31, 630–639 (2010).
Martino, C. F. Static magnetic field sensitivity of endothelial cells. Bioelectromagnetics 32, 506–508 (2011).
Li, F. et al. Pulsed magnetic field accelerate proliferation and migration of cardiac microvascular endothelial cells. Bioelectromagnetics 36, 1–9 (2015).
Zhao, M., Bai, H., Wang, E., Forrester, J. V. & McCaig, C. D. Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J. Cell Sci. 117, 397–405 (2004).
Takahashi, K., Doge, F. & Yoshioka, M. Prolonged Ca2+ transients in ATP-stimulated endothelial cells exposed to 50 Hz electric fields. Cell Biol. Int. 29, 237–243 (2005).
Shin, D. W. et al. In vivo modulation of the blood-brain barrier permeability by transcranial direct current stimulation (tDCS). Ann. Biomed. Eng. 48, 1256–1270 (2020).
Tarkowski, E. et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol. Aging 23, 237–243 (2002).
Cieślak, M. & Wojtczak, A. Role of purinergic receptors in the Alzheimer’s disease. Purinergic Signal 14, 331–344 (2018).
Quintana, D. D. et al. Amyloid-β causes mitochondrial dysfunction via a Ca2+-driven upregulation of oxidative phosphorylation and superoxide production in cerebrovascular endothelial cells. J. Alzheimers Dis. 75, 119–138 (2020).
Grammas, P. et al. A new paradigm for the treatment of Alzheimer’s disease: targeting vascular activation. J. Alzheimers Dis. 40, 619–630 (2014).
Hong, Y. et al. High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats. J. Neuroinflammation 17, 150 (2020).
Kinzenbaw, D. A., Chu, Y., Peña Silva, R. A., Didion, S. P. & Faraci, F. M. Interleukin-10 protects against aging-induced endothelial dysfunction. Physiol. Rep. 1, e00149 (2013).
Zenaro, E., Piacentino, G. & Constantin, G. The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 107, 41–56 (2017).
Rezai, A. R. et al. Noninvasive hippocampal blood-brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc. Natl Acad. Sci. USA 117, 9180–9182 (2020).
Shin, J. et al. Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimers Res. Ther. 11, 110 (2019).
Lipsman, N. et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 9, 2336 (2018).
Ravnborg, M., Knudsen, G. M. & Blinkenberg, M. No effect of pulsed magnetic stimulation on the blood-brain barrier in rats. Neuroscience 38, 277–280 (1990).
Vazana, U. et al. Glutamate-mediated blood-brain barrier opening: implications for neuroprotection and drug delivery. J. Neurosci. 36, 7727–7739 (2016).
Vazana, U. et al. TMS-induced controlled BBB opening: preclinical characterization and implications for treatment of brain cancer. Pharmaceutics 12, 946 (2020).
Crismon, M. L. Pharmacokinetics and drug interactions of cholinesterase inhibitors administered in Alzheimer’s disease. Pharmacotherapy 18, 47–54, discussion 79–82 (1998).
Bahr-Hosseini, M. & Bikson, M. Neurovascular-modulation: a review of primary vascular responses to transcranial electrical stimulation as a mechanism of action. Brain Stimul. 14, 837–847 (2021).
Nitsche, M. A. et al. MRI study of human brain exposed to weak direct current stimulation of the frontal cortex. Clin. Neurophysiol. 115, 2419–2423 (2004).
Sher, I. et al. Repetitive magnetic stimulation protects corneal epithelium in a rabbit model of short-term exposure keratopathy. Ocul. Surf. 18, 64–73 (2020).
Azis, I. A. et al. Electroconvulsive shock restores the decreased coverage of brain blood vessels by astrocytic endfeet and ameliorates depressive-like behavior. J. Affect. Disord. 257, 331–339 (2019).
Zong, X. et al. Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization. Theranostics 10, 12090–12110 (2020).
Goulay, R., Mena Romo, L., Hol, E. M. & Dijkhuizen, R. M. From stroke to dementia: a comprehensive review exposing tight interactions between stroke and amyloid-β formation. Transl. Stroke Res. 11, 601–614 (2020).
Martino, C. F., Perea, H., Hopfner, U., Ferguson, V. L. & Wintermantel, E. Effects of weak static magnetic fields on endothelial cells. Bioelectromagnetics 31, 296–301 (2010).
Özyurt, M. G., Bayir, E., DoĞan, Ş., ÖztÜrk, Ş. & Şendemİr, A. Coculture model of blood-brain barrier on electrospun nanofibers. Turk. J. Biol. 44, 121–132 (2020).
Cancel, L. M., Arias, K., Bikson, M. & Tarbell, J. M. Direct current stimulation of endothelial monolayers induces a transient and reversible increase in transport due to the electroosmotic effect. Sci. Rep. 8, 9265 (2018).
Gunn, C. K. Hereditary acholuric jaundice in the rat. Can. Med. Assoc. J. 50, 230–237 (1944).
Labrune, P., Myara, A., Trivin, F. & Odievre, M. Gunn rats: a reproducible experimental model to compare the different methods of measurements of bilirubin serum concentration and to evaluate the risk of bilirubin encephalopathy. Clin. Chim. Acta 192, 29–33 (1990).
Weber, R. Z. et al. Characterization of the blood brain barrier disruption in the photothrombotic stroke model. Front. Physiol. 11, 586226 (2020).
Ortiz, G. G. et al. Role of the blood-brain barrier in multiple sclerosis. Arch. Med. Res. 45, 687–697 (2014).
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R. & Zlokovic, B. V. Blood-brain barrier: from physiology to disease and back. Physiol. Rev. 99, 21–78 (2019).
Wicha, P., Das, S. & Mahakkanukrauh, P. Blood-brain barrier dysfunction in ischemic stroke and diabetes: the underlying link, mechanisms and future possible therapeutic targets. Anat. Cell Biol. 54, 165–177 (2021).
Beisteiner, R. & Lozano, A. M. Transcranial ultrasound innovations ready for broad clinical application. Adv. Sci. 7, 2002026 (2020).
Fishman, P. S. & Fischell, J. M. Focused ultrasound mediated opening of the blood-brain barrier for neurodegenerative diseases. Front. Neurol. 12, 749047 (2021).
Shin, D. W. et al. In vivo modulation of the blood–brain barrier permeability by transcranial direct current stimulation (tDCS). Ann. Biomed. Eng. 48, 1256–1270 (2020).
Xia, Y., Li, Y., Khalid, W., Bikson, M. & Fu, B. M. Direct current stimulation disrupts endothelial glycocalyx and tight junctions of the blood-brain barrier in vitro. Front. Cell Dev. Biol. 9, 731028 (2021).
Acknowledgements
This work is an output of a research project implemented as part of the Basic Research Program at the National Research University Higher School of Economics (HSE University) and was carried out using HSE Automated system of non-invasive brain stimulation with the possibility of synchronous registration of brain activity and registration of eye movements. We are grateful to our colleagues, PhD Irina Petrushanko and PhD Evgene Barykin, for rigorous reading of the manuscript and fruitful discussions. We also esteem the assistance of Anastasia Asmolova and Peter Young in English version editing. Figures 1 and 2 were created with BioRender.com.
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A.P. and M.N. conceptualized the manuscript and wrote it; A.T. wrote the manuscript and prepared the figures; A.M. prepared an English version of the manuscript. A.P., A.T., A.M., and M.N. discussed the results and commented on the manuscript, read, and approved the submitted version.
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Petrovskaya, A., Tverskoi, A., Medvedeva, A. et al. Is blood-brain barrier a probable mediator of non-invasive brain stimulation effects on Alzheimer’s disease?. Commun Biol 6, 416 (2023). https://doi.org/10.1038/s42003-023-04717-1
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DOI: https://doi.org/10.1038/s42003-023-04717-1
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