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Specific amyloid ? clearance by a catalytic antibody construct.

ABSTRACT: Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid ? (A?)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the A? C terminus noncovalently and hydrolyzed A? rapidly, with no reactivity to the A? precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive A? dipeptide unit. The catabody dissolved preformed A? aggregates and inhibited A? aggregation more potently than an A?-binding IgG. Intravenous catabody treatment reduced brain A? deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific A? hydrolysis appears to be an innate immune function that could be applied for therapeutic A? removal.

SUBMITTER: Planque SA

PROVIDER: S-EPMC4400338 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Specific amyloid β clearance by a catalytic antibody construct.

Planque Stephanie A SA Nishiyama Yasuhiro Y Sonoda Sari S Lin Yan Y Taguchi Hiroaki H Hara Mariko M Kolodziej Steven S Mitsuda Yukie Y Gonzalez Veronica V Sait Hameetha B R HB Fukuchi Ken-ichiro K Massey Richard J RJ Friedland Robert P RP O'Nuallain Brian B Sigurdsson Einar M EM Paul Sudhir S

The Journal of biological chemistry 20150227 16

Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid β (Aβ)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aβ C terminus noncovalently and hydrolyzed Aβ rapidly, with no reactivity to the Aβ precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containi ...[more]

PMID: 25724648

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Project description:BackgroundMicroglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.MethodsHere we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.ResultsWe show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.ConclusionThese results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.

Project description:The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also via endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1-integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin+/-). However, the reduction of Aβ load in APP/PS1;cofilin+/- mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin+/- mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation via dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-β clearance.

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Specific amyloid ? clearance by a catalytic antibody construct.

Publications

Specific amyloid β clearance by a catalytic antibody construct.

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