The toxicity of β-amyloid is attenuated by interaction with its specific human scFv E3 in vitro

Shen, Ya; Li, Yue; Wang, Xiaohua; Bai, Hui; Xia, Jun; Jiang, Li; Ji, Yong; Fan, Ligang; He, Zhisong; Chen, Qi

doi:10.1016/j.lfs.2008.04.009

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…According to this theory, Rozga et al stated that the relative abundance of the low affinity HSA in serum is responsible for the aggregation-inhibiting effect on peripheral Aβ. In contrast, a specific Aβ-binding reagent should be able to inhibit aggregation at equimolar concentrations due to its higher affinity to Aβ [24]. Indeed, we could show that 22C4 scFv reduced Aβ aggregation even in substoichiometric concentration and it did so to a greater extent than the non-specific BSA (Figure S3B).…”

Section: Discussionmentioning

confidence: 83%

“…This construct can easily be expressed in E. coli [23], rendering scFv production efficient and cost-effective. Previous in vitro studies demonstrated that scFv were capable of inhibiting Aβ 1-42 aggregation and preventing Aβ-induced neurotoxicity [24], [25], [26], [27], [28]. In addition, two in vivo studies showed that scFv can ameliorate amyloid pathology after stereotaxic injection into the hippocampus and cortex of Tg2576 mice [29] or after intracranial adeno-associated virus-mediated delivery of an anti-pan amyloid-beta scFv in TgCRND8 mice [30].…”

Section: Introductionmentioning

confidence: 99%

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Chronic Intranasal Treatment with an Anti-Aβ30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

et al. 2011

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Amyloid-beta peptide (Aβ)-directed active and passive immunization therapeutic strategies reduce brain levels of Aβ, decrease the severity of beta-amyloid plaque pathology and reverse cognitive deficits in mouse models of Alzheimer's disease (AD). As an alternative approach to passive immunization with full IgG molecules, single-chain variable fragment (scFv) antibodies can modulate or neutralize Aβ-related neurotoxicity and inhibit its aggregation in vitro. In this study, we characterized a scFv derived from a full IgG antibody raised against the C-terminus of Aβ, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aβ-related pathology. We found that the scFv entered the brain after intranasal application, and that it bound to beta-amyloid plaques in the cortex and hippocampus of APP transgenic mice. Moreover, the scFv inhibited Aβ fibril formation and Aβ-mediated neurotoxicity in vitro. In a preventative therapeutic approach chronic intranasal treatment with scFv reduced congophilic amyloid angiopathy (CAA) and beta-amyloid plaque numbers in the cortex of APPswe/PS1dE9 mice. This reduction of CAA and plaque pathology was associated with a redistribution of brain Aβ from the insoluble fraction to the soluble peptide pool. Due to their lack of the effector domain of full IgG, scFv may represent an alternative tool for the treatment of Aβ-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aβ-directed immunotherapy can reduce Aβ deposition in brain vessels in transgenic mice.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Chronic Intranasal Treatment with an Anti-Aβ30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

et al. 2011

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“…Thus, these antibodies can be considered a new approach for the treatment of this brain disorder 72. 73 It was shown that a recombinant mouse/rat chimeric MAb against the mouse transferrin receptor, namely cTfRMAb, crossed the BBB in mice 74. Fusion of a single chain fragment variable (ScFv) anti‐Aβ MAb to cTfRMAb enabled it to penetrate the BBB in mice following i.p.…”

Section: Molecular Trojan Horsesmentioning

confidence: 99%

Shuttle‐Mediated Drug Delivery to the Brain

Malakoutikhah¹,

Teixidó²,

Giralt³

2011

Angew Chem Int Ed

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Advances in the field of shuttle-mediated drug delivery have been made in the last decade; however, the treatment of brain disorders still remains a great challenge because of the presence of the blood-brain barrier (BBB), a structure that limits the access of drugs to their site of action in the central nervous system. Several strategies have been proposed to enhance the transport of drugs across the BBB. In this Review, we focus on the vector-mediated approach, in which a drug is coupled to a molecule (shuttle) that has the ability to cross the BBB and deliver the drug to the brain.

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“…Man kann diese Antikçrper also als neuen Ansatz für die Behandlung dieser Gehirnerkrankung ansehen. [72,73] Ein rekombinanter chimärer Maus-/Ratte-MAb gegen den murinen Transferrin-Rezeptor mit der Bezeichnung cTfRMAb passiert die BHS in Mäusen. [74] Eine Fusion eines Einzelkettenfragments mit der variablen Region gegen Ab aus einem monoklonalen Antikçrper (ScFv anti-Ab) mit cTfRMAb ermçglichte den Übergang über die BHS nach intraperitonealer Injektion in Mäusen, wobei die Bindungsaffinität für das AbAmyloidpeptid erhalten blieb.…”

Section: Molekulare Trojanische Pferdeunclassified

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

2011

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Während des letzten Jahrzehnts wurden im Bereich der Wirkstofffreisetzung wesentliche Fortschritte erzielt. Die Behandlung von Gehirnerkrankungen bleibt aber wegen der Blut‐Hirn‐Schranke (BHS; blood–brain barrier) noch immer eine große Herausforderung. Diese Struktur schränkt den Zugang von Wirkstoffen zu ihrem Wirkort im Zentralnervensystem stark ein. Es wurden verschiedene Strategien vorgeschlagen, um den Transport von Wirkstoffen über die BHS zu verstärken. In diesem Aufsatz konzentrieren wir uns auf einen vektorvermittelten Ansatz, bei dem der Wirkstoff an ein Schleusermolekül gekuppelt wird, das die Fähigkeit hat, die BHS zu überqueren und die Substanz ins Gehirn abzugeben.

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The toxicity of β-amyloid is attenuated by interaction with its specific human scFv E3 in vitro

Cited by 7 publications

References 53 publications

Chronic Intranasal Treatment with an Anti-Aβ30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Chronic Intranasal Treatment with an Anti-Aβ30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Shuttle‐Mediated Drug Delivery to the Brain

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

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