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Immunization targeting a minor plaque constituent clears ?-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model.

ABSTRACT: Although anti-human ?-amyloid (A?) immunotherapy clears brain ?-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine A? is a minor A? plaque component in amyloid precursor protein (APP) transgenic AD models, which we show is ?3%-8% of the total accumulated A? in various human APP transgenic mice. Murine A? codeposits and colocalizes with human A? in amyloid plaques, and the two A? species coimmunoprecipitate together from brain extracts. In the human APP transgenic mouse model Tg2576, passive immunization for 8 weeks with a murine-A?-specific antibody reduced ?-amyloid plaque pathology, robustly decreasing both murine and human A? levels. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine A? immunization clears A? plaque pathology--including the major human A? component--and decreases behavioral deficits, arguing that targeting minor endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.

SUBMITTER: Morales-Corraliza J

PROVIDER: S-EPMC3426627 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model.

Morales-Corraliza Jose J Schmidt Stephen D SD Mazzella Matthew J MJ Berger Jason D JD Wilson Donald A DA Wesson Daniel W DW Jucker Mathias M Levy Efrat E Nixon Ralph A RA Mathews Paul M PM

Neurobiology of aging 20120518 1

Although anti-human β-amyloid (Aβ) immunotherapy clears brain β-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine Aβ is a minor Aβ plaque component in amyloid precursor protein (APP) transgenic AD models, which we show is ∼3%-8% of the total accumulated Aβ in various human APP transgenic mice. Murine Aβ codeposits and colocalizes with human Aβ in amyloid plaques, and the two Aβ species coimmu ...[more]

PMID: 22608241

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Project description:BACKGROUND:Amyloid ? (A?)-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 A? peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such A? variants have been initiated. Modified A? represents a small fraction of deposited material in plaques compared to pan-A? epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize L-isoaspartate-modified A? (isoD7-A?) and tested a lead antibody molecule in 5xFAD mice. METHODS:This work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. A? 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-A? monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-A? ELISA as well as different non-modified A? ELISA. For antibody treatment studies, 12?mg/kg anti-isoD7-A? 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. RESULTS:Our advanced antibody K11 showed a KD in the low nM range and?>?400fold selectivity for isoD7-A? compared to other A? variants. By using this antibody, we demonstrated that formation of isoD7-A? may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged A? 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-A? in cell culture. The presence of isoD7-A? 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-A? and total A? 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-A? epitope, the application of anti-isoD7-A? antibodies showed comparable treatment efficacy in terms of reduction of brain amyloid and spatial learning but did not result in an increase of plasma A? concentration as observed with 3D6 treatment. CONCLUSIONS:The present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified A? peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified A?, the results highlight the crucial role of modified A? peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.

Project description:Although lots of new drugs are developed to treat Alzheimer's disease (AD), many clinical trials of monotherapy have failed to affect disease progression or symptoms compared with placebo. Recently, scientists believe that combination treatment is more promising than monotherapy. Previous studies found that microRNA-195 (miR-195) was down-regulated in the hippocampi and cortices of chronic brain hypoperfusion (CBH) rats and ApoE4(+/+) mice, and up-regulation of miR-195 can improve the declined cognitive function of ApoE4(+/+) mice and CBH rats by targeting multi-genes that are related to AD pathology, including amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) genes. However, whether the gain-of-function of miR-195 could improve the impaired learning and memory ability of APP/PS1 transgenic mouse has not been reported. In this study, we stereotaxically injected lentiviral-carried miR-195 into the bilateral hippocampus of 4-month-old (4M) APP/PS1 mice. Morris water maze (MWM) was performed to detect the effect of miR-195 on the cognitive function of APP/PS1 mice after 1M, 2M, and 3M treatment. Western blot was used to detect the expression of APP, BACE1, and AT8. Aβ plagues were quantitatively assessed by immunofluorescence technique. We found that the declined cognitive phenotype of APP/PS1 mice occurred at the age of 6M, not at the age of 5M. And treatment of Lv-pre-miR-195 to APP/PS1 mice for 1M did not achieve any changes. Although Lv-pre-miR-195 treatment for 2M improved the declined learning ability of APP/PS1 mice, it did not affect the memory functions. However, Lv-pre-miR-195 treatment in APP/PS1 mice for 3M can effectively improve both the learning and memory ability of APP/PS1 mice at the age of 7M. Further studies demonstrated that gain-of-function of miR-195 by Lv-pre-miR-195 injection could inhibit the increased APP and AT8 expression of APP/PS1 mice but did not affect BACE1 level that was not changed in both hippocampus and cortex. By counting the number of Aβ plaques of different sizes, we found that Lv-pre-miR-195 treatment mainly reduced the number of Aβ plaques of less than 20 μm, but did not affect the number of Aβ plaques of greater than 50 μm. Taken together, the gain-of -function of miR-195 in the hippocampus can improve the cognition of APP/PS1 mice, probably by blocking the formation of Aβ plagues rather than clearing those that have already formed Aβ plagues.

Project description:BACKGROUND:Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce A? without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined A? plaque formation and reactive gliosis in these mice. RESULTS:In the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive A? plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human A?40 and A?42 in their brains. CONCLUSIONS:A? plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.

Dataset Information

Immunization targeting a minor plaque constituent clears ?-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model.

Publications

Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model.

Similar Datasets

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