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Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies.

ABSTRACT: Recent work from our lab and few others have strongly suggested that immunotherapy could be an effective means of preventing the development of tau accumulation in JNPL3 transgenic mice, carrying the human P301L mutation. The aim of this study was to test the efficacy of a variety of specific tau monoclonal antibodies in JNPL3. Starting at 3 months of age, mice were treated for 4 months with weekly intraperitoneal injections of saline or purified tau monoclonal antibodies (10 mg/Kg) different in specificity for pathological tau: CP13 (pSer202), RZ3 (pThr231) and PG5 (pSer409). As expected, not all the antibodies tested showed efficacy at preventing the development of tau pathology at the described dose, with some of them even worsening the pathological scenario. Only by targeting the pSer202 epitope with CP13 was a conspicuous reduction of insoluble or soluble tau in cortex and hindbrain obtained. Here we report about the importance of screening in vivo multiple tau antibodies in order to select the antibodies to direct into future clinical studies.

SUBMITTER: d'Abramo C

PROVIDER: S-EPMC4536019 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies.

d'Abramo Cristina C Acker Christopher M CM Jimenez Heidy H Davies Peter P

PloS one 20150813 8

Recent work from our lab and few others have strongly suggested that immunotherapy could be an effective means of preventing the development of tau accumulation in JNPL3 transgenic mice, carrying the human P301L mutation. The aim of this study was to test the efficacy of a variety of specific tau monoclonal antibodies in JNPL3. Starting at 3 months of age, mice were treated for 4 months with weekly intraperitoneal injections of saline or purified tau monoclonal antibodies (10 mg/Kg) different in ...[more]

PMID: 26270821

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Project description:Accumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6-18 and 77E9 against tau 184-195 on tau and amyloid-? (A?) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.We immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 ?g of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and A? pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.We found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing A?40 and A?42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding A? plaques.These findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6-18 as a disease-modifying approach to AD and related tauopathies.

Dataset Information

Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies.

Publications

Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies.

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