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Article ; Online: Erythrocyte-brain endothelial interactions induce microglial responses and cerebral microhemorrhages in vivo.

Zhang, Hai / Sumbria, Rachita K / Chang, Rudy / Sun, Jiahong / Cribbs, David H / Holmes, Todd C / Fisher, Mark J / Xu, Xiangmin

Journal of neuroinflammation

2023 Volume 20, Issue 1, Page(s) 265

Abstract: Background: Cerebral microhemorrhages (CMH) are associated with stroke, cognitive decline, and normal aging. Our previous study shows that the interaction between oxidatively stressed red blood cells (RBC) and cerebral endothelium may underlie CMH ... ...

Abstract	Background: Cerebral microhemorrhages (CMH) are associated with stroke, cognitive decline, and normal aging. Our previous study shows that the interaction between oxidatively stressed red blood cells (RBC) and cerebral endothelium may underlie CMH development. However, the real-time examination of altered RBC-brain endothelial interactions in vivo, and their relationship with clearance of stalled RBC, microglial responses, and CMH development, has not been reported. Methods: RBC were oxidatively stressed using tert-butylhydroperoxide (t-BHP), fluorescently labeled and injected into adult Tie2-GFP mice. In vivo two-photon imaging and ex vivo confocal microscopy were used to evaluate the temporal profile of RBC-brain endothelial interactions associated with oxidatively stressed RBC. Their relationship with microglial activation and CMH was examined with post-mortem histology. Results: Oxidatively stressed RBC stall significantly and rapidly in cerebral vessels in mice, accompanied by decreased blood flow velocity which recovers at 5 days. Post-mortem histology confirms significantly greater RBC-cerebral endothelial interactions and microglial activation at 24 h after t-BHP-treated RBC injection, which persist at 7 days. Furthermore, significant CMH develop in the absence of blood-brain barrier leakage after t-BHP-RBC injection. Conclusions: Our in vivo and ex vivo findings show the stalling and clearance of oxidatively stressed RBC in cerebral capillaries, highlighting the significance of microglial responses and altered RBC-brain endothelial interactions in CMH development. Our study provides novel mechanistic insight into CMH associated with pathological conditions with increased RBC-brain endothelial interactions.
MeSH term(s)	Mice ; Animals ; Microglia ; Brain/blood supply ; Erythrocytes ; Cerebral Hemorrhage ; Endothelium
Language	English
Publishing date	2023-11-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-023-02932-5
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Article: The Effects of a Blood-Brain Barrier Penetrating Erythropoietin in a Mouse Model of Tauopathy.

Yang, Joshua / Ou, Weijun / Jagadeesan, Nataraj / Simanauskaite, Juste / Sun, Jiahong / Castellanos, Demi / Cribbs, David H / Sumbria, Rachita K

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 4

Abstract: Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer's disease (AD) but has limited blood-brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the ... ...

Abstract	Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer's disease (AD) but has limited blood-brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline;
Language	English
Publishing date	2023-04-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16040558
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Article ; Online: Cerebral Blood Flow in Chronic Kidney Disease.

Choi, Bernard / Crouzet, Christian / Lau, Wei Ling / Cribbs, David H / Fisher, Mark J

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

2021 Volume 30, Issue 9, Page(s) 105702

Abstract: The prevalence of mild cognitive impairment increases with age and is further exacerbated by chronic kidney disease (CKD). CKD is associated with (1) mild cognitive impairment, (2) impaired endothelial function, (3) impaired blood-brain barrier, (4) ... ...

Abstract	The prevalence of mild cognitive impairment increases with age and is further exacerbated by chronic kidney disease (CKD). CKD is associated with (1) mild cognitive impairment, (2) impaired endothelial function, (3) impaired blood-brain barrier, (4) increased cerebral microhemorrhage burden, (5) increased cerebral blood flow (CBF), (6) impaired cerebral autoregulation, (7) impaired cerebrovascular reactivity, and (8) increased arterial stiffness. We report preliminary findings from our group that demonstrate altered cerebrovascular reactivity in a mouse model of CKD-associated vascular calcification. The CBF of CKD mice increased more quickly in response to hypercapnia (p < 0.05) but then decreased prematurely during hypercapnia challenge (p < 0.05). Together, these results indicate that altered kidney function can lead to alterations in the cerebral microvasculature, and hence brain health.
MeSH term(s)	Animals ; Cerebral Arteries/physiopathology ; Cerebrovascular Circulation ; Cerebrovascular Disorders/etiology ; Cerebrovascular Disorders/physiopathology ; Cognition ; Cognitive Dysfunction/etiology ; Cognitive Dysfunction/physiopathology ; Cognitive Dysfunction/psychology ; Disease Models, Animal ; Female ; Homeostasis ; Humans ; Hypercapnia/complications ; Hypercapnia/physiopathology ; Kidney/physiopathology ; Mice, Inbred DBA ; Microcirculation ; Renal Insufficiency, Chronic/complications ; Renal Insufficiency, Chronic/physiopathology ; Mice
Language	English
Publishing date	2021-03-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1131675-5
ISSN	1532-8511 ; 1052-3057
ISSN (online)	1532-8511
ISSN	1052-3057
DOI	10.1016/j.jstrokecerebrovasdis.2021.105702
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Article ; Online: Abeta DNA vaccination for Alzheimer's disease: focus on disease prevention.

Cribbs, David H

CNS & neurological disorders drug targets

2010 Volume 9, Issue 2, Page(s) 207–216

Abstract: Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants ... ...

Abstract	Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Adjuvants, Immunologic/therapeutic use ; Alzheimer Disease/immunology ; Alzheimer Disease/prevention & control ; Alzheimer Vaccines/adverse effects ; Alzheimer Vaccines/genetics ; Alzheimer Vaccines/therapeutic use ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/immunology ; Animals ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Clinical Trials as Topic/statistics & numerical data ; Humans ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Vaccination/methods ; Vaccination/trends ; Vaccines, DNA/adverse effects ; Vaccines, DNA/immunology ; Vaccines, DNA/therapeutic use
Chemical Substances	Adjuvants, Immunologic ; Alzheimer Vaccines ; Amyloid beta-Peptides ; Antibodies, Monoclonal ; Vaccines, DNA
Language	English
Publishing date	2010-03-02
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2228394-8
ISSN	1996-3181 ; 1871-5273
ISSN (online)	1996-3181
ISSN	1871-5273
DOI	10.2174/187152710791012080
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Article ; Online: Chronic kidney disease promotes cerebral microhemorrhage formation.

Fang, Chuo / Lau, Wei Ling / Sun, Jiahong / Chang, Rudy / Vallejo, Adrian / Lee, Donghy / Liu, Jihua / Liu, Han / Hung, Yu-Han / Zhao, Yitong / Paganini-Hill, Annlia / Sumbria, Rachita K / Cribbs, David H / Fisher, Mark

Journal of neuroinflammation

2023 Volume 20, Issue 1, Page(s) 51

Abstract: Background: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo ... ...

Abstract	Background: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. Methods: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. Results: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). Conclusions: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.
MeSH term(s)	Animals ; Female ; Male ; Mice ; Brain ; Creatinine/adverse effects ; Mice, Inbred C57BL ; Renal Insufficiency, Chronic ; Uremic Toxins ; Intracranial Hemorrhages
Chemical Substances	Creatinine (AYI8EX34EU) ; Uremic Toxins
Language	English
Publishing date	2023-02-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-023-02703-2
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Article ; Online: Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.

Zagorski, Karen / King, Olga / Hovakimyan, Armine / Petrushina, Irina / Antonyan, Tatevik / Chailyan, Gor / Ghazaryan, Manush / Hyrc, Krzysztof L / Chadarevian, Jean Paul / Davtyan, Hayk / Blurton-Jones, Mathew / Cribbs, David H / Agadjanyan, Michael G / Ghochikyan, Anahit

International journal of molecular sciences

2023 Volume 24, Issue 12

Abstract: Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 ( ... ...

Abstract	Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/prevention & control ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Pyrrolidonecarboxylic Acid ; Cancer Vaccines ; Immunotherapy ; Plaque, Amyloid/pathology ; Brain/metabolism ; Mice, Transgenic ; Disease Models, Animal
Chemical Substances	Amyloid beta-Peptides ; Pyrrolidonecarboxylic Acid (SZB83O1W42) ; Cancer Vaccines
Language	English
Publishing date	2023-06-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24129797
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Article: Simple methodology to visualize whole-brain microvasculature in three dimensions.

Khouri, Katiana / Xie, Danny F / Crouzet, Christian / Bahani, Adrian W / Cribbs, David H / Fisher, Mark J / Choi, Bernard

Neurophotonics

2021 Volume 8, Issue 2, Page(s) 25004

Abstract: Significance: ...

Abstract	Significance:
Language	English
Publishing date	2021-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2781943-7
ISSN	2329-4248 ; 2329-423X
ISSN (online)	2329-4248
ISSN	2329-423X
DOI	10.1117/1.NPh.8.2.025004
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Article ; Online: Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer's Disease.

Kirouac, Lisa / Rajic, Alexander J / Cribbs, David H / Padmanabhan, Jaya

eNeuro

2017 Volume 4, Issue 2

Abstract: It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer's disease (AD), yet little is known about the contribution of APP to intracellular signaling ... ...

Abstract	It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer's disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Aβ42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Aβ generation, denotes a vicious feedforward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/enzymology ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/administration & dosage ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain/drug effects ; Brain/enzymology ; Brain/pathology ; Cell Line, Tumor ; Cyclin D1/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Glycogen Synthase Kinase 3/metabolism ; Humans ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology ; Male ; Nerve Degeneration/enzymology ; Nerve Degeneration/pathology ; Neurons/drug effects ; Neurons/enzymology ; Neurons/pathology ; Peptide Fragments/administration & dosage ; Peptide Fragments/metabolism ; Phosphorylation ; Rats, Sprague-Dawley ; ras Proteins/metabolism ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; MAPT protein, human ; Mapt protein, rat ; Peptide Fragments ; amyloid beta-protein (1-42) ; tau Proteins ; Cyclin D1 (136601-57-5) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0149-16.2017
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Article ; Online: Author Correction: Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies.

Kim, Changyoun / Hovakimyan, Armine / Zagorski, Karen / Antonyan, Tatevik / Petrushina, Irina / Davtyan, Hayk / Chailyan, Gor / Hasselmann, Jonathan / Iba, Michiyo / Adame, Anthony / Rockenstein, Edward / Szabo, Marcell / Blurton-Jones, Mathew / Cribbs, David H / Ghochikyan, Anahit / Masliah, Eliezer / Agadjanyan, Michael G

NPJ vaccines

2023 Volume 8, Issue 1, Page(s) 105

Language	English
Publishing date	2023-07-17
Publishing country	England
Document type	Published Erratum
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-023-00703-0
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Article ; Online: Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates.

Hovakimyan, Armine / Zagorski, Karen / Chailyan, Gor / Antonyan, Tatevik / Melikyan, Levon / Petrushina, Irina / Batt, Dash G / King, Olga / Ghazaryan, Manush / Donthi, Aashrit / Foose, Caitlynn / Petrovsky, Nikolai / Cribbs, David H / Agadjanyan, Michael G / Ghochikyan, Anahit

NPJ vaccines

2022 Volume 7, Issue 1, Page(s) 117

Abstract: Pathological forms of Tau protein are directly associated with neurodegeneration and correlate with Alzheimer's Disease (AD) symptoms, progression, and severity. Previously, using various mouse models of Tauopathies and AD, we have demonstrated the ... ...

Abstract	Pathological forms of Tau protein are directly associated with neurodegeneration and correlate with Alzheimer's Disease (AD) symptoms, progression, and severity. Previously, using various mouse models of Tauopathies and AD, we have demonstrated the immunogenicity and efficacy of the MultiTEP-based adjuvanted vaccine targeting the phosphatase activating domain (PAD) of Tau, AV-1980R/A. Here, we analyzed its immunogenicity in non-human primates (NHP), the closest phylogenic relatives to humans with a similar immune system, to initiate the transition of this vaccine into clinical trials. We have demonstrated that AV-1980R/A is highly immunogenic in these NHPs, activating a broad but unique to each monkey repertoire of MultiTEP-specific T helper (Th) cells that, in turn, activate B cells specific to PAD. The resulting anti-PAD IgG antibodies recognize pathological Tau tangles and Tau-positive neuritis in AD case brain sections with no staining in control non-AD cases. These published data and efficacy results support the AV-1980R/A vaccine progression to first-in-human clinical trials.
Language	English
Publishing date	2022-10-12
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-022-00544-3
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