TARGETING THE SHARED PATHOLOGICAL CONFORMERS OF BOTH Aβ AND HYPERPHOSPHYLATED TAU WITH A CONFORMATIONALLY SELECTIVE MONOCLONAL ANTIBODY

Abstract

Background: Pathological tau aggregation leading to filamentous tau inclusions characterizes neurodegenerative tauopathies such as Alzheimer’s Disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Tau aggregation is linked with clinical symptoms and probably represents the mediator of neurodegeneration. At the moment there is no cure for these diseases and existing treatments are only of palliative nature. Methods: Transgenic mice that overexpress human P301S tau mutation resemble many neuropathological features of human tauopathies in combination with behavioral deficits and increased mortality. We tested the effect of the small molecule anle138b as an anti-aggregative drug on the neuropathology and behavioral deficits in P301S mice. The compound was administered from weaning until death. Results: Here we show that reducing the amount of tau aggregates using the compound anle138b ameliorates disease symptoms in a mousemodel for tauopathies. Treatment with anle138b significantly prolonged the survival of transgenic mice and rescued behavioral deficits as well as synapse and neuron loss in the CA3 region and stratum lucidum of the hippocampus. Our results indicate that reducing tau pathology with the anti-aggregative compound anle138b represents a clinically effective and promising approach for the treatment of human tauopathies. Conclusions: In conclusion, anle138b mitigate tau pathology and may represent a new lead compound for developing a therapy for human tauopathies.