Drug Discovery

Clearance of Pathological Tau Conformers

Investigator(s): Einar M. Sigurdsson, PhD

Institution(s): NYU School of Medicine

Duration: 2008 - 2009

Summary:

Immunotherapies that target the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) have consistently resulted in Abeta clearance and cognitive improvements in mouse studies, and this effect is likely to be mediated by antibodies. 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 Abeta 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 Abeta and tau pathologies are likely synergistic. Hence, targeting both pathologies at the same time may be more effective. Also, Abeta immunotherapy does not reduce tau aggregates in AD or mouse models, showing the importance of developing a separate tangle-targeting therapy. Our findings in the P301L tangle mouse model indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Clearance of extracellular tangles may reduce associated pathology and several reports of neuronal uptake of antibodies suggest that intracellular tangles and pre-tangles may also be affected. In addition, we demonstrate that these antibodies enter the brain and bind to pathological tau based on their colocalization with AD specific tau antibodies. Recent findings from a related field support our approach. Like tau in AD, alpha-synuclein aggregates intracellularly in Parkinson's disease brain, and immunization with alpha-synuclein has been shown to clear these aggregates in transgenic (Tg) mice.
Specific Aim 1 is to improve the therapeutic effect of active immunization against pathological tau conformers by evaluating various tau-derived immunogens in Tg mouse tangle models. Immune response, behavior, tau biochemistry and histology as well as associated pathology will be assessed. Overall, these studies should lead to valuable findings on which type of tau immunotherapy is likely to be safe and effective, and should identify the appropriate tau immunogen for use in clinical trials.

 

Specific Aim 2 is to monitor treatment efficacy with manganese-enhanced magnetic resonance imaging. Longitudinal study will be performed in P301L Tg mice that receive the most effective immunogen as well as in controls. The objective is to determine the feasibility of monitoring treatment efficacy in vivo. Our preliminary findings support this approach and indicate that this type of in vivo imaging reveals age-dependent neuronal dysfunction in the hippocampus in the P301L Tg model of tauopathy, compared to age-matched wild-type control mice. In addition to its potential utility for quickly evaluating various therapies in vivo, this approach should provide important information on the effect of tau aggregation on neural activity in live animals.