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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032611-05
Application #
8309170
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Miller, Marilyn
Project Start
2008-08-01
Project End
2013-09-29
Budget Start
2012-08-01
Budget End
2013-09-29
Support Year
5
Fiscal Year
2012
Total Cost
$329,444
Indirect Cost
$135,082
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Sigurdsson, Einar M (2014) Tau immunotherapy and imaging. Neurodegener Dis 13:103-6
Gu, Jiaping; Congdon, Erin E; Sigurdsson, Einar M (2013) Two novel Tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce Tau protein pathology. J Biol Chem 288:33081-95
Bertrand, Anne; Khan, Umer; Hoang, Dung M et al. (2013) Non-invasive, in vivo monitoring of neuronal transport impairment in a mouse model of tauopathy using MEMRI. Neuroimage 64:693-702
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Rajamohamedsait, Hameetha B; Sigurdsson, Einar M (2012) Histological staining of amyloid and pre-amyloid peptides and proteins in mouse tissue. Methods Mol Biol 849:411-24
Boutajangout, Allal; Li, Yong Sheng; Quartermain, David et al. (2012) Cognitive and sensorimotor tasks for assessing functional impairments in mouse models of Alzheimer's disease and related disorders. Methods Mol Biol 849:529-40
Boutajangout, A; Sigurdsson, E M; Krishnamurthy, P K (2011) Tau as a therapeutic target for Alzheimer's disease. Curr Alzheimer Res 8:666-77
Boutajangout, Allal; Ingadottir, Johanna; Davies, Peter et al. (2011) Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem 118:658-67
Krishnamurthy, Pavan K; Sigurdsson, Einar M (2011) Therapeutic applications of antibodies in non-infectious neurodegenerative diseases. N Biotechnol 28:511-7

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