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Aβ peptide immunization restores blood‐brain barrier integrity in Alzheimer disease
Abstract
Immunization with amyloid beta (Abeta) peptides or passive immunization with antibodies against Abeta has been reported to reduce plaque burden, neuritic dystrophy, early Tau pathology, microgliosis as well as reversing learning and memory deficits. This has created a central paradox: how does vaccination in peripheral tissues reduce plaque burden in the brain? No single explanation for these phenomena has yet been presented. To reconcile these observations, we demonstrate that the integrity of the blood-brain barrier (BBB), a structural barrier between the brain and the blood, is compromised in Tg2576 Alzheimer disease (AD) model mice. We immunized Tg2576 mice with Abeta before and after the onset of AD-type neuropathology and observed that BBB permeability, amyloid burden, and microgliosis are decreased in immunized mice. It is concluded that the integrity of the BBB is disrupted in AD mice, and after Abeta immunization the immune system clears Abeta from sources in the brain as it would in peripheral organs lacking barriers. Once Abeta is removed, the integrity of the BBB is restored. The data therefore provide an intellectual framework for understanding how the immune system can clear amyloid deposits from AD brains and suggest new strategies for limiting disease progression in amyloidopathies.
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“impairments of the BBB have been observed in this context (Dickstein et al., 2006; Zipser et al., 2007; Lassman et al., 2012; Figure 2).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Dickstein et al., 2006
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“It has already been shown that the elimination of Aβ from the brain and the consequent impairment of microglial activation decrease ROS, nitrogen compounds and also inflammatory cytokines produced by microglial cells, which are correlated with the activation of ECs (Dickstein et al., 2006).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Dickstein et al., 2006
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“Along the same line, Dickstein et al. (2006) demonstrated that Aβ immunization therapy could restore BBB integrity in the same AD mouse model (Tg2576), in addition to improvement of typical AD brain pathological features such as plaque burden and microgliosis, suggesting a new strategy for AD…”
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“The authors suggested that one possible clearance mechanism might be via plasma gelsolin entrance into brain parenchyma across the BBB, as reports have indicated that the BBB is compromised in mouse models of AD [42].”
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“preceding hypervascularization, tight junction disruption and BBB dysfunction [27, 28] and that active Aβ immunization reverse these pathological events [29, 30].”
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“In addition, active AA immunization was shown to a reverse these microvascular pathologic events (51, 52).”
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“Beyond doubts, microglial activation is substantially involved in BBB impairments during the progression of neurodegenerative diseases, including Alzheimer ́s disease and multiple sclerosis (McGeer and McGeer, 1995; Dickstein et al., 2006; Zipser et al., 2007; Lassmann et al., 2012).”
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Kumar‐Singh, S. (2009) · International Journal of Molecular Sciences · doi:10.3390/ijms10041872 · Cited by 40
Nanoparticles as Contrast Agents for The Diagnosis of Alzheimer’s Disease: A Systematic Review
Ulanova, M., Poljak, A., Wen, W. X., Bongers, A., Gloag, L., Gooding, J. J., Tilley, R. D., Sachdev, P. S., & Braidy, N. (2020) · Nanomedicine · doi:10.2217/nnm-2019-0316 · Cited by 39
Singh, C. S. B., Choi, K. B., Munro, L., Wang, H. Y., Pfeifer, C. G., & Jefferies, W. A. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103503 · Cited by 36
“Finally, BBB leakage first noted in this model [7,10,12,14] has recently been proposed as an early biomarker in patients with AD [38,39].”
BackgroundButtmann, M., Lorenz, A., Weishaupt, A., & Rieckmann, P. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04563.x · Cited by 35
Lyons, A., Murphy, K. J., Clarke, R. M., & Lynch, M. A. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-27 · Cited by 34
“BBB permeability has been shown to be compromised in a mouse model of Alzheimer’s disease [24], while soluble Ab has been shown to stimulate inflammatory changes in the vasculature [25] and to permit monocyte infiltration into the brain [26].”
BackgroundImmunotherapy as treatment for Alzheimer’s disease
Hawkes, C. A., & McLaurin, J. (2007) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.7.11.1535 · Cited by 33
Vascular Endothelial Barrier Dysfunction Mediated by Amyloid-β Proteins
Nagababu, E., Usatyuk, P. V., Enika, D., Natarajan, V., & Rifkind, J. M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1104 · Cited by 32
“In animal models, the impaired integrity of the BBB has been shown to be restored following immunization with antibodies against A β implicating vascular A β in the impaired BBB of these animals [8].”
InfluentialCessation of Neoangiogenesis in Alzheimer's Disease Follows Amyloid-beta Immunization
Biron, K. E., Dickstein, D. L., Gopaul, R., Fenninger, F., & Jefferies, W. A. (2013) · Scientific Reports · doi:10.1038/srep01354 · Cited by 34
Pluta, R. M. (2008) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s3739 · Cited by 32
“…2005; Pluta et al 2006) and exposure to the potentially neurotoxic peptide probably initiates amyloid plaques formation/maturation (Kawai et al 1990; Dickstein et al 2006) with further additional neuronal cell death (Koistinaho et al 2002) and massive neuronal network destruction (Iwasaki et al…”
Amtul, Z., & Hepburn, J. D. (2014) · Reviews in the Neurosciences · doi:10.1515/revneuro-2013-0041 · Cited by 30
Jeynes, B., & Provias, J. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0099-z · Cited by 31
“numerous investigators have suggested that a breakdown of the BBB may contribute to lesion development, particularly as it relates to amyloid deposition [15, 16, 21, 27, 38, 49, 50, 67, 72, 80].”
BackgroundConsideration of the ischaemic basis and treatment of Alzheimer's disease.
Pluta, R. M., Ułamek, M., & Jabłoński, M. (2010) · PubMed · Cited by 29
Ryu, J., Tran, K., & McLarnon, J. (2007) · Glia · doi:10.1002/glia.20479 · Cited by 30
“Altered BBB integrity induced by QUIN was also examined by assessing extravasation of Evans blue dye (Dickstein et al., 2006).”
MethodImmunotherapy in Alzheimer's Disease: Where Do We Stand? Where Should We Go?
Rommy von Bernhardi, M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1248 · Cited by 28
The antimicrobial protein, CAP37, is upregulated in pyramidal neurons during Alzheimer’s disease
Brock, A. J., Kasus‐Jacobi, A., Lerner, M. R., Logan, S., Adesina, A. M., & Pereira, H. A. (2015) · Histochemistry and Cell Biology · doi:10.1007/s00418-015-1347-x · Cited by 26
“Many pathogens that cause chronic infections have been found to compromise the blood–brain barrier which is disrupted in AD (Dickstein et al. 2006; van Sorge and Doran 2012; Erickson and Banks 2013; Marques et al. 2013; White et al. 2014).”
BackgroundAmtul, Z., Yang, J., Lee, T., & Cechetto, D. F. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00047 · Cited by 26
Vargas-Rodríguez, P., Cuenca-Martagón, A., Castillo-González, J., Serrano-Martínez, I., Luque, R. M., Delgado, M., & González-Rey, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814117 · Cited by 25
Hinge, N. S., Kathuria, H., & Pandey, M. M. (2021) · Applied Materials Today · doi:10.1016/j.apmt.2021.101303 · Cited by 25
Mentor, S., & Fisher, D. W. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.938315 · Cited by 24
“This model is supported by a study by (Dickstein et al., 2006) who reported that immunization of Alzheimer’s disease mouse strains with antibodies against amyloid beta peptides could restore BBB integrity by decreasing the permeability across the BBB.”
ResultFinke, J. M., & Banks, W. A. (2016) · Human Antibodies · doi:10.3233/hab-160306 · Cited by 23
“First, some studies supported the premise that the BBB becomes “leaky” or more permissive to passage as AD progresses [48,56,78,93, 164].”
Pluta, R. M., Miziak, B., & Czuczwar, S. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310739 · Cited by 22
“AD are referred to as leukoaraiosis [11,35,36,80].”
BackgroundInfluentialLin, M., Zhu, L., Wang, J., Xue, Y., & Shang, X. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.07.075 · Cited by 21
Ryu, J. K., & McLarnon, J. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-18 · Cited by 626
“A second method determined infiltration of Evans blue dye through a leaky BBB and followed published procedures [26, 27 ].”
Immunotherapy and Neuroimmunology in Alzheimer‘s Disease: a Perspective from The Blood–Brain Barrier
Banks, W. A. (2009) · Immunotherapy · doi:10.2217/imt.09.72 · Cited by 15
Singh, C. S. B., Johns, K. M., Kari, S., Munro, L., Mathews, A., Fenninger, F., Pfeifer, C. G., & Jefferies, W. A. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2024.02.012 · Cited by 13
“…model is much more rapid than in the AD mice as it is established in the AD bone marrow recipients in 6 months compared to 12 months in the AD transgenic mice (Biron et al., 2011, 2013; Dickstein et al., 2006; Hsiao et al., 1996; Jefferies et al., 2013; Singh et al., 2021; Ujiie et al., 2003).”
Development of vaccination approaches for the treatment of neurological diseases
Federoff, H. J. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22034 · Cited by 13
Anuradha, U., Angati, A., Gautam, A. S., Dey, M., Pandey, S. K., & Singh, R. K. (2023) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2023.2256840 · Cited by 9
“Evans’s blue method was performed according to Dickstein et al. (2006).”
MethodAlzheimer's Factors in Ischemic Brain Injury
Pluta, R. M., & Jaboski, M. (2012) · InTech eBooks · doi:10.5772/27205 · Cited by 9
“Aforementioned data suggest that reducing movement of -amyloid peptide from blood to brain tissue (Dickstein et al., 2006) and significantly improving reverse transport from brain into blood plasma (Pluta et al.”
BackgroundInfluentialBabušíková, E., Evinová, A., Hatok, J., Dobrota, D., & Jurecekov, J. (2013) · InTech eBooks · doi:10.5772/54619 · Cited by 8
Evaluation of blood-brain barrier permeability in tryptophan hydroxylase 2-knockout mice
Xu, C., PengZhang, DAI, T.-L., Niu, X., Wang, J., Jin, M.-S., & Min-Liao (2014) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2014.1938 · Cited by 6
How to Stabilize Both the Proteins and the Membranes: Diverse Effects of sHsps in Neuroprotection
Tóth, M. E., Sántha, M., Penke, B., & Vı́gh, L. (2015) · Heat shock proteins · doi:10.1007/978-3-319-16077-1_23 · Cited by 6
Xing, X., Sha, S., Chen, X.-H., Guo, W., Guo, R., Jiang, T., & Cao, Y. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1559-4 · Cited by 5
“Studies showed that the integrity of the BBB is disrupted in AD mice, and after Ab immunization the immune system clears Ab from sources in the brain as it would in peripheral organs lacking barriers, and the integrity of the BBB is restored after Ab removing [24].”
Metadata
- Authors
- Dickstein, D. L., Biron, K. E., Ujiie, M., Pfeifer, C. G., Jeffries, A. R., & Jefferies, W. A.
- Affiliations
- University of British Columbia (CA)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2006-03
- Volume
- 20
- Issue
- 3
- Pages
- 426-433
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2021255508
- Cited by
- 111
- References
- 52
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 5 · 2012: 4
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Update notices
- erratum (2006-07-01)
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta immunization, blood-brain barrier integrity, Alzheimer's disease, Tg2576 mice, blood-brain barrier permeability, amyloid plaque clearance, microglial activation, amyloid pathology, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Blood-Brain Barrier, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Organ Specificity, Peptide Fragments, Vaccination, Amyloid beta-Peptides, Microglia, Mice, Plaque, Amyloid
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