Tauopathies are a family of neurodegenerative disorders characterized by the intracellular aggregation of filaments predominantly composed of hyperphosphorylated microtubule-associated protein tau. This family of neurodegenerative disorders includes Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with Parkinsonism linked to chromosome 17 and Pick disease, among others. Genetics, biochemical and neuropathological studies suggest that disruption of the biological function of tau proteins, either by mutations, hyperphosphorylation and/or aberrant protein interactions, may play a central role in the process of neurodegeneration. However, the molecular mechanisms underlying tau- mediated neurodegeneration are still poorly understood. Recently, the PI's research group has demonstrated that Amphiphysin-1 (AMPH1) protein level is significantly reduced in the tauopathy mouse model JNPL3 and AD cases. The reduction in AMPH1 protein level is associated with detection of pathological tau in terminally ill JNPL3 mice and AD. AMPH1 is a scaffold protein essential for clatherin-coated vesicle endocytosis, which plays an important role in synaptic activity and its deletion leads to cognitive impairment. Importantly, the presence of anti-AMPH1 antibodies in human serum has been correlated with a neurological disorder known as Stiff-person-syndrome. The autoimmune response that leads to the generation of anti-AMPH1 antibodies is unknown. Preliminary studies showed that terminally ill JNPL3 mice generated detectable self-AMPH1 antibodies in the serum. The detection of the self-AMPH1 antibodies correlates with reduction in the level of AMPH1 protein, suggesting that neurodegeneration in this tauopathy mouse model may lead to the disruption of self-tolerance mechanisms. Therefore, in order to characterize and validate the production of autoimmune antibodies in tau-mediated neurodegeneration the following two specific objectives will be addressed: (1) To characterize and validate the autoimmune response that lead to self-AMPH1 antibodies in tauopathies;(2) To identify autoimmune biomarkers in tau-mediated neurodegeneration. The results obtained will contribute to the identification of disease-specific protein biomarkers that could serve as diagnostic tools and for the better understanding of the pathobiology of tau-mediated neurodegeneration. Importantly, the research plan provides an opportunity to train undergraduate and graduates students on the importance of translating basic biomedical research into applied research in the quest to provide insights on diseases that afflict the general population, such as AD.
The development of non-invasive diagnostic tools for neurodegenerative disorders, such as Alzheimer's disease and other tauopathies, is crucial for the testing of new forms of treatment that may prevent, retard or revert the progression of these diseases. The proposed research plan intends to characterize and validate the identification of autoimmune responses in the course of tau-mediated neurodegeneration. The results obtained may lead to the discovery of disease-specific protein biomarkers that serve as diagnostic tools and to better understand the pathobiology of tauopathies.