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  1. Article ; Online: A Chronic Increase in Blood-Brain Barrier Permeability Facilitates Intraneuronal Deposition of Exogenous Bloodborne Amyloid-Beta1-42 Peptide in the Brain and Leads to Alzheimer's Disease-Relevant Cognitive Changes in a Mouse Model.

    Acharya, Nimish K / Grossman, Henya C / Clifford, Peter M / Levin, Eli C / Light, Kenneth R / Choi, Hana / Swanson Ii, Randel L / Kosciuk, Mary C / Venkataraman, Venkat / Libon, David J / Matzel, Louis D / Nagele, Robert G

    Journal of Alzheimer's disease : JAD

    2024  Volume 98, Issue 1, Page(s) 163–186

    Abstract: Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1-42) (Aβ42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes ... ...

    Abstract Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1-42) (Aβ42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood.
    Objective: To test the hypothesis that chronic extravasation of bloodborne Aβ42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model.
    Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aβ42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes.
    Results: Mice injected with both PT and Aβ42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls.
    Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.
    MeSH term(s) Male ; Mice ; Animals ; Blood-Brain Barrier/metabolism ; Alzheimer Disease/pathology ; Peptide Fragments/toxicity ; Peptide Fragments/metabolism ; Brain/pathology ; Amyloid beta-Peptides/metabolism ; Cognition ; Immunoglobulin G/metabolism
    Chemical Substances Peptide Fragments ; Amyloid beta-Peptides ; Immunoglobulin G
    Language English
    Publishing date 2024-02-22
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-231028
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Histamine Induces Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures.

    Sedeyn, Jonathan C / Wu, Hao / Hobbs, Reilly D / Levin, Eli C / Nagele, Robert G / Venkataraman, Venkat

    BioMed research international

    2015  Volume 2015, Page(s) 937148

    Abstract: Among the top ten causes of death in the United States, Alzheimer's disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism ...

    Abstract Among the top ten causes of death in the United States, Alzheimer's disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses-a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin-were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/chemically induced ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/pathology ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Histamine/metabolism ; Histamine/pharmacology ; Histamine/toxicity ; Humans ; Male ; Mice ; Neurons/metabolism ; Neurons/pathology ; Organ Culture Techniques ; Vimentin/metabolism
    Chemical Substances Glial Fibrillary Acidic Protein ; Vimentin ; glial fibrillary astrocytic protein, mouse ; Histamine (820484N8I3)
    Language English
    Publishing date 2015-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2698540-8
    ISSN 2314-6141 ; 2314-6133
    ISSN (online) 2314-6141
    ISSN 2314-6133
    DOI 10.1155/2015/937148
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Brain-reactive autoantibodies are nearly ubiquitous in human sera and may be linked to pathology in the context of blood-brain barrier breakdown.

    Levin, Eli C / Acharya, Nimish K / Han, Min / Zavareh, Semah B / Sedeyn, Jonathan C / Venkataraman, Venkateswar / Nagele, Robert G

    Brain research

    2010  Volume 1345, Page(s) 221–232

    Abstract: Previous studies have reported antibodies bound to cells in postmortem Alzheimer's disease (AD) brains, which are only rarely observed in the brains of healthy, age-matched controls. This implies that brain-reactive autoantibodies exist in the sera of AD ...

    Abstract Previous studies have reported antibodies bound to cells in postmortem Alzheimer's disease (AD) brains, which are only rarely observed in the brains of healthy, age-matched controls. This implies that brain-reactive autoantibodies exist in the sera of AD individuals and can gain access to the brain interstitium. To investigate this possibility, we determined the prevalence of brain-reactive antibodies in sera from AD patients, patients with other neurodegenerative diseases, age-matched, non-demented controls and healthy younger individuals via immunohistochemistry and western blot analysis. Surprisingly, western analyses revealed that 92% of all human sera tested contain brain-reactive autoantibodies. When sera were used to probe western blots of human, pig, or rat brain membrane proteins, a number of comparably-sized protein targets were detected, suggesting cross-species reactivity. While the presence of brain-reactive autoantibodies was nearly ubiquitous in human sera, some autoantibodies appeared to be associated with age or disease. Furthermore, the intensity of antibody binding to brain tissue elements, especially the surfaces of neurons, correlated more closely to the serum's autoantibody profile than to age or the presence of neurodegenerative disease. However, while the blood-brain barrier (BBB) in control brains remained intact, BBB breakdown was common in AD brains. Results suggest a high prevalence of brain-reactive antibodies in human sera which, in the common context of BBB compromise, leads us to propose that these antibodies may contribute to the initiation and/or pathogenesis of AD and other neurodegenerative diseases.
    MeSH term(s) Adult ; Age Factors ; Aged ; Aged, 80 and over ; Alzheimer Disease/immunology ; Alzheimer Disease/pathology ; Animals ; Autoantibodies/blood ; Autoantibodies/immunology ; Blood-Brain Barrier/immunology ; Blood-Brain Barrier/pathology ; Blotting, Western ; Brain/immunology ; Brain/pathology ; Case-Control Studies ; Cross Reactions ; Humans ; Immunoglobulin G/immunology ; Immunohistochemistry ; Middle Aged ; Models, Neurological ; Neurodegenerative Diseases/immunology ; Neurons/immunology ; Neurons/pathology ; Rats ; Rats, Sprague-Dawley ; Swine ; Young Adult
    Chemical Substances Autoantibodies ; Immunoglobulin G
    Language English
    Publishing date 2010-07-23
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2010.05.038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Neuronal expression of vimentin in the Alzheimer's disease brain may be part of a generalized dendritic damage-response mechanism.

    Levin, Eli C / Acharya, Nimish K / Sedeyn, Jonathan C / Venkataraman, Venkateswar / D'Andrea, Michael R / Wang, Hoau-Yan / Nagele, Robert G

    Brain research

    2009  Volume 1298, Page(s) 194–207

    Abstract: Early pathological features of Alzheimer's disease (AD) include synaptic loss and dendrite retraction, prior to neuronal loss. How neurons respond to this evolving AD pathology remains elusive. In the present study, we used single- and double-label ... ...

    Abstract Early pathological features of Alzheimer's disease (AD) include synaptic loss and dendrite retraction, prior to neuronal loss. How neurons respond to this evolving AD pathology remains elusive. In the present study, we used single- and double-label immunohistochemistry to investigate the relationship between neuronal vimentin expression and local brain pathology. Vimentin was localized to neuronal perikarya and dendrites in AD brain, with vimentin-immunopositive neurons prevalent in regions exhibiting intra- and extracellular beta-amyloid(1-42) (Abeta42) deposition. Neuronal co-localization of vimentin and Abeta42 was common in the cerebral cortex, cerebellum and hippocampus. Additionally, neurons in affected brain regions of AD transgenic (Tg2576) mice and in brain tissue subjected to mechanical injury expressed vimentin, while those in comparable regions of control mouse brain did not. Finally, we show that neurons in human fetal brain express vimentin concurrently with periods of rapid neurite extension. Overall, our results suggest that neurons express vimentin as part of an evolutionarily conserved, damage-response mechanism which recapitulates a developmental program used by differentiating neurons to establish dendrites and synaptic connections.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism ; Cell Count ; Cell Differentiation/physiology ; Dendrites/metabolism ; Female ; Humans ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurofibrillary Tangles/metabolism ; Plaque, Amyloid/metabolism ; Time Factors ; Vimentin/metabolism
    Chemical Substances Amyloid beta-Peptides ; Vimentin
    Language English
    Publishing date 2009-11-17
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2009.08.072
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Alpha7 nicotinic acetylcholine receptor expression by vascular smooth muscle cells facilitates the deposition of Abeta peptides and promotes cerebrovascular amyloid angiopathy.

    Clifford, Peter M / Siu, Gilbert / Kosciuk, Mary / Levin, Eli C / Venkataraman, Venkateswar / D'Andrea, Michael R / Nagele, Robert G

    Brain research

    2008  Volume 1234, Page(s) 158–171

    Abstract: Deposition of beta-amyloid (Abeta) peptides in the walls of brain blood vessels, cerebral amyloid angiopathy (CAA), is common in patients with Alzheimer's disease (AD). Previous studies have demonstrated Abeta peptide deposition among vascular smooth ... ...

    Abstract Deposition of beta-amyloid (Abeta) peptides in the walls of brain blood vessels, cerebral amyloid angiopathy (CAA), is common in patients with Alzheimer's disease (AD). Previous studies have demonstrated Abeta peptide deposition among vascular smooth muscle cells (VSMCs), but the source of the Abeta and basis for its selective deposition in VSMCs are unknown. In the present study, we examined the deposition patterns of Abeta peptides, Abeta40 and Abeta42, within the cerebrovasculature of AD and control patients using single- and double-label immunohistochemistry. Abeta40 and Abeta42 were abundant in VSMCs, especially in leptomeningeal arteries and their initial cortical branches; in later-stage AD brains this pattern extended into the microvasculature. Abeta peptide deposition was linked to loss of VSMC viability. Perivascular leak clouds of Abeta-positive material were associated primarily with arterioles. By contrast, control brains possessed far fewer Abeta42- and Abeta40-immunopositive blood vessels, with perivascular leak clouds of Abeta-immunopositive material rarely observed. We also demonstrate that VSMCs in brain blood vessels express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), which has high binding affinity for Abeta peptides, especially Abeta42. These results suggest that the blood and blood-brain barrier permeability provide a major source of the Abeta peptides that gradually deposit in brain VSMCs, and the presence and abundance of the alpha7nAChR on VSMCs may facilitate the selective accumulation of Abeta peptides in these cells.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Arterioles/metabolism ; Arterioles/pathology ; Blood-Brain Barrier/physiology ; Cell Survival ; Cerebral Amyloid Angiopathy/metabolism ; Cerebral Amyloid Angiopathy/pathology ; Cerebral Arteries/metabolism ; Cerebral Arteries/pathology ; Entorhinal Cortex/pathology ; Female ; Hippocampus/pathology ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Receptors, Nicotinic/biosynthesis ; alpha7 Nicotinic Acetylcholine Receptor
    Chemical Substances Amyloid beta-Peptides ; Chrna7 protein, human ; Receptors, Nicotinic ; alpha7 Nicotinic Acetylcholine Receptor
    Language English
    Publishing date 2008-10-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2008.07.092
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  6. Article ; Online: Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib.

    Acharya, Nimish K / Levin, Eli C / Clifford, Peter M / Han, Min / Tourtellotte, Ryan / Chamberlain, Dean / Pollaro, Michael / Coretti, Nicholas J / Kosciuk, Mary C / Nagele, Eric P / Demarshall, Cassandra / Freeman, Theresa / Shi, Yi / Guan, Chenbing / Macphee, Colin H / Wilensky, Robert L / Nagele, Robert G

    Journal of Alzheimer's disease : JAD

    2013  Volume 35, Issue 1, Page(s) 179–198

    Abstract: Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of ...

    Abstract Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of advanced coronary atherosclerosis in a porcine model, and that treatment with darapladib, an inhibitor of lipoprotein-associated phospholipase A2, blocks atherosclerosis progression and improves animal alertness and activity levels. In the present study, we examined the effects of DM and HC on the permeability of the blood-brain barrier (BBB) using immunoglobulin G (IgG) as a biomarker. DMHC increased BBB permeability and the leak of microvascular IgG into the brain interstitium, which was bound preferentially to pyramidal neurons in the cerebral cortex. We also examined the effects of DMHC on the brain deposition of amyloid peptide (Aβ42), a well-known pathological feature of Alzheimer's disease. Nearly all detectable Aβ42 was contained within cortical pyramidal neurons and DMHC increased the density of Aβ42-loaded neurons. Treatment of DMHC animals with darapladib reduced the amount of IgG-immunopositive material that leaked into the brain as well as the density of Aβ42-containing neurons. Overall, these results suggest that a prolonged state of DMHC may have chronic deleterious effects on the functional integrity of the BBB and that, in this DMHC pig model, darapladib reduces BBB permeability. Also, the preferential binding of IgG and coincident accumulation of Aβ42 in the same neurons suggests a mechanistic link between the leak of IgG through the BBB and intraneuronal deposition of Aβ42 in the brain.
    MeSH term(s) 1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors ; 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Benzaldehydes/pharmacology ; Benzaldehydes/therapeutic use ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Capillary Permeability/drug effects ; Capillary Permeability/physiology ; Diabetes Mellitus/drug therapy ; Diabetes Mellitus/metabolism ; Diabetes Mellitus/pathology ; Hypercholesterolemia/drug therapy ; Hypercholesterolemia/metabolism ; Hypercholesterolemia/pathology ; Oximes/pharmacology ; Oximes/therapeutic use ; Peptide Fragments/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Swine ; Treatment Outcome
    Chemical Substances Amyloid beta-Peptides ; Benzaldehydes ; Oximes ; Peptide Fragments ; amyloid beta-protein (1-42) ; 1-Alkyl-2-acetylglycerophosphocholine Esterase (EC 3.1.1.47) ; darapladib (UI1U1MYH09)
    Language English
    Publishing date 2013
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-122254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition.

    Nagele, Robert G / Clifford, Peter M / Siu, Gilbert / Levin, Eli C / Acharya, Nimish K / Han, Min / Kosciuk, Mary C / Venkataraman, Venkat / Zavareh, Semah / Zarrabi, Shabnam / Kinsler, Kristin / Thaker, Nikhil G / Nagele, Eric P / Dash, Jacqueline / Wang, Hoau Y / Levitas, Andrew

    Journal of Alzheimer's disease : JAD

    2011  Volume 25, Issue 4, Page(s) 605–622

    Abstract: Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies ...

    Abstract Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.
    MeSH term(s) Aged ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; Animals ; Autoantibodies/blood ; Blood-Brain Barrier ; Blotting, Western ; Brain/immunology ; Female ; Humans ; Image Processing, Computer-Assisted ; Immunoglobulin G/metabolism ; Immunohistochemistry ; Male ; Mice ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Organ Culture Techniques ; Peptide Fragments/metabolism ; Pyramidal Cells/metabolism ; Rats ; Rats, Sprague-Dawley
    Chemical Substances Amyloid beta-Peptides ; Autoantibodies ; Immunoglobulin G ; Nerve Tissue Proteins ; Peptide Fragments ; amyloid beta-protein (1-42)
    Language English
    Publishing date 2011
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-2011-110098
    Database MEDical Literature Analysis and Retrieval System OnLINE

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