Immunotherapies that target the amyloid-? (A?) peptide in Alzheimer's disease (AD) have consistently resulted in A? clearance and cognitive improvements in mouse studies. Clinical trials using this approach were halted because of encephalitis observed in a small subset of patients but promising preliminary findings have emerged from this trial. These include reduction in A? burden and cognitive stabilization. Refinement of this approach is currently underway, and additional clinical trials have been initiated by several companies. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. Histological analysis in AD brains and mouse models indicate that A? and tau pathologies are likely synergistic. Hence, targeting both pathologies at the same time may be more effective. Also, A? immunotherapy does not reduce tau aggregates in AD or mouse models, showing the importance of developing a separate tangle-targeting therapy. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons.
Specific Aim 1 is to improve the therapeutic effect of active immunization against pathological tau conformers, clarify its mechanism and to determine if this approach can reverse tau pathology. Tangle models (P301L and htau) will be immunized with tau derivatives prior to or following the onset of pathology. Immune response, behavior, tau biochemistry and histology as well as associated pathology will be assessed. Concurrently, the mechanism of antibody-mediated clearance will be studied in 1) tangle mice in vivo;and 2) a brain slice tangle model. These studies should clarify which type of tau immunotherapy is likely to be safe and effective, and should identify an immunogen for clinical trials.
Specific Aim 2 is to determine how tau aggregates and their clearance influence neural activity in vivo, and to monitor treatment efficacy with manganese-enhanced magnetic resonance imaging (MEMRI). Longitudinal study will be performed in tangle mice that receive the most effective immunogen and controls. MEMRI is a novel non-invasive technique to image neural activity that has not been used in tangle models. Our preliminary data shows an increased and decreased manganese uptake in young and old P301L mice, respectively (36% difference, p<0.001), compared to normal controls. MEMRI should clarify the effects of tau aggregates on neuronal function and may allow a rapid in vivo evaluation of therapeutic approaches targeting pathological tau aggregates, which may substantially shorten these experiments.

Public Health Relevance

There is currently no effective treatment for Alzheimer's disease.
The aim of this proposal is to develop further therapy that targets neurofibrillary tangles and/or their pathological tau precursors, which are one of the major hallmarks of the disease. Furthermore, we propose to develop an in vivo imaging technique that will clarify the neurotoxic effects of tau aggregates, and this approach may be used to monitor therapy in live animals and possibly to diagnose the disease in the future.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Miller, Marilyn
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New York University
Schools of Medicine
New York
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Bertrand, Anne; Baron, Maria; Hoang, Dung M et al. (2018) In Vivo Evaluation of Neuronal Transport in Murine Models of Neurodegeneration Using Manganese-Enhanced MRI. Methods Mol Biol 1779:527-541
Chukwu, Jessica E; Pedersen, Jan T; Pedersen, Lars Ø et al. (2018) Tau Antibody Structure Reveals a Molecular Switch Defining a Pathological Conformation of the Tau Protein. Sci Rep 8:6209
Krishnaswamy, Senthilkumar; Wu, Qian; Lin, Yan et al. (2018) In Vivo Imaging of Tauopathy in Mice. Methods Mol Biol 1779:513-526
Wu, Qian; Lin, Yan; Gu, Jiaping et al. (2018) Dynamic assessment of tau immunotherapies in the brains of live animals by two-photon imaging. EBioMedicine 35:270-278
Shamir, Dov B; Deng, Yan; Sigurdsson, Einar M (2018) Live Imaging of Pathological Tau Protein and Tau Antibodies in a Neuron-Like Cellular Model. Methods Mol Biol 1779:371-379
Sigurdsson, Einar M (2018) Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Progress and Potential Pitfalls. J Alzheimers Dis 64:S555-S565
Congdon, Erin E; Sigurdsson, Einar M (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14:399-415
Rajamohamedsait, Hameetha; Rasool, Suhail; Rajamohamedsait, Wajitha et al. (2017) Prophylactic Active Tau Immunization Leads to Sustained Reduction in Both Tau and Amyloid-? Pathologies in 3xTg Mice. Sci Rep 7:17034
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Krishnamurthy, Pavan K; Rajamohamedsait, Hameetha B; Gonzalez, Veronica et al. (2016) Sex and Immunogen-Specific Benefits of Immunotherapy Targeting Islet Amyloid Polypeptide in Transgenic and Wild-Type Mice. Front Endocrinol (Lausanne) 7:62

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