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Pyroglutamate amyloid ? (A?) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

ABSTRACT: Pyroglutamate-modified A? peptides at amino acid position three (A?(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). A?(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated A?(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces A?(pE3-42). TBA42 mice showed age-dependent behavioral deficits and A?(pE3-42) accumulation. The A? profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified A? peptides: A?(1-42), A?(1-40), A?(pE3-40), A?(pE3-42), A?(3-42), A?(4-42), and A?(5-42). 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that A?(pE3) levels were elevated in FAD42 mice. No change in A?(x)(-42) or other A? isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of A?(pE-42) in FAD42 mice.

SUBMITTER: Wittnam JL

PROVIDER: S-EPMC3318696 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

Wittnam Jessica L JL Portelius Erik E Zetterberg Henrik H Gustavsson Mikael K MK Schilling Stephan S Koch Birgit B Demuth Hans-Ulrich HU Blennow Kaj K Wirths Oliver O Bayer Thomas A TA

The Journal of biological chemistry 20120120 11

Pyroglutamate-modified Aβ peptides at amino acid position three (Aβ(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aβ(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aβ(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produc ...[more]

PMID: 22267726

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Project description:BackgroundAmyloid β (Aβ)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified Aβ peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such Aβ variants have been initiated. Modified Aβ represents a small fraction of deposited material in plaques compared to pan-Aβ epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize L-isoaspartate-modified Aβ (isoD7-Aβ) and tested a lead antibody molecule in 5xFAD mice.MethodsThis work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. Aβ peptides, containing L-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-Aβ monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-Aβ ELISA as well as different non-modified Aβ ELISA. For antibody treatment studies, 12 mg/kg anti-isoD7-Aβ antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38 weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze.ResultsOur advanced antibody K11 showed a KD in the low nM range and > 400fold selectivity for isoD7-Aβ compared to other Aβ variants. By using this antibody, we demonstrated that formation of isoD7-Aβ may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged Aβ from newly formed peptides. Importantly, we also show that the Tottori mutation responsible for early-onset AD in a Japanese pedigree is characterized by massively accelerated formation of isoD7-Aβ in cell culture. The presence of isoD7-Aβ was verified by K11 in post mortem human cortex and 5xFAD mouse brain tissue. Passive immunization of 5xFAD mice resulted in a significant reduction of isoD7-Aβ and total Aβ in brain. Amelioration of cognitive impairment was demonstrated by Morris water maze, elevated plus maze, pole, and contextual fear conditioning tests. Interestingly, despite the lower abundance of the isoD7-Aβ epitope, the application of anti-isoD7-Aβ antibodies showed comparable treatment efficacy in terms of reduction of brain amyloid and spatial learning but did not result in an increase of plasma Aβ concentration as observed with 3D6 treatment.ConclusionsThe present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified Aβ, the results highlight the crucial role of modified Aβ peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.

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Pyroglutamate amyloid ? (A?) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

Publications

Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

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