NOVEL THERAPEUTIC TARGETS TO MITIGATE EARLY NEURONAL DYSFUNCTION AND COGNITIVE DEFICITS IN TAUOPATHY
- John Koren, United States of America
Abstract
Aims
Tauopathies are a group of more than twenty known neurodegenerative disorders that affect millions of people worldwide. There is no cure for tauopathies, and current therapeutic strategies provide limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression.
Methods
We treated tau transgenic mice with a multi-target kinase inhibitor to identify novel targets that contribute to cognitive impairment and putative therapeutic targets.
Results
Treatment significantly ameliorated neuronal function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to compare this model with known changes in AD, to identify protein changes similar to known AD alterations calcium, mitochondrial, and metabolic/bioenergetic pathways as highly vulnerable. This is the first characterization of pathway networks altered in this tauopathic mouse model as well as the networks responsive to multi-target kinase inhibition. These analyses reveal pathways associated with cognitive function across tauopathies. We identified disease proteins that are consistent between the tauopathic mouse and human proteome.
Conclusions
Our results further demonstrate the novel therapeutic potential of diminishing nitroxidative stress and highlight its involvement in driving the early stages of neuronal and cognitive dysfunction found in neurodegeneration. Additionally, we identified four proteins displaying a pathological overlap between mouse models of AD and persons with AD.