Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models
| Autor: | Alan Lin, Vangipuram S. Rangan, Nestor X. Barrezueta, Laurel Vana, Paul D. Wes, Magdalena Nitla, Angela Cacace, Stefanie Keenan, Bin Zhang, Bradley Snyder, Nina Hoque, John Q. Trojanowski, Donna M. Barten, Jere E. Meredith, Ling Yang, Charles F. Albright, Craig Polson, Lynn B. DeCarr, Gregg Hirschfeld, Virginia M.-Y. Lee, Michael K. Ahlijanian, Gregory W. Cadelina, Kurt R. Brunden, Nino Devidze, Sethu Sankaranarayanan, Yang Cao |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Male Pathology medicine.medical_specialty Tau protein Primary Cell Culture Hippocampus lcsh:Medicine Mice Transgenic tau Proteins Biology Mice Alzheimer Disease mental disorders medicine Animals lcsh:Science Cerebral Cortex Neurons Multidisciplinary lcsh:R Immunization Passive Antibodies Monoclonal Entorhinal cortex medicine.disease Phosphoproteins Recombinant Proteins Disease Models Animal medicine.anatomical_structure Treatment Outcome Gene Expression Regulation Cerebral cortex biology.protein Exploratory Behavior lcsh:Q Neuron Tauopathy Alzheimer's disease Cognition Disorders Signal Transduction Research Article |
| Zdroj: | PLoS ONE, Vol 10, Iss 5, p e0125614 (2015) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies. |
| Databáze: | OpenAIRE |
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