Research

RESEARCH

The investigators in the Tau Consortium bring together a wide variety of research skills and expertise through active collaboration across laboratories. This breadth of this effort allows us to study tau from multiple perspectives. We quickly share information with each other in order to speed our understanding of tau-related neurodegeneration. Currently, we are investigating eight different approaches to understanding healthy and disease-causing tau.

Tau Production (RNA Silencing)

These studies on the production of tau focus on lowering the overall levels of tau in the brain and spinal cord. A human clinical trial in Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS) with an antisense oligonucleotide against another disease-causing gene, SOD1, has been completed and is the model for a similar trial in patients with tauopathies. The antisense oligonucleotide acts to decrease total tau production in the brain, thereby decreasing the amount of tau available to misfold.


Tau Propagation

Toxic tau aggregates may spread cell-to-cell along specific networks, in a prion-like fashion, leading to progressive brain dysfunction. Tau microdialysis, a new method to measure tau in the brain of active mice, has shown that neuronal communication rapidly increases tau in the space surrounding nerve cells in the brain. Investigators are using genome-wide association studies (GWAS) of the spinal fluid to look for tau “seeding” and any new genetic risk factors.


Tau Clearance (Autophagy & Proteosome)

These studies focus on removing toxic forms of tau from the brain by using the cell’s normal cleaning process (via autophagy, or the proteasome). If the process of tau is unable to remove toxic tau (or does it too slowly), abnormal concentrations of tau appear, injuring or killing the neuron. We have identified targets in the autophagy and proteosome pathways as potential drug targets to speed up the rate of tau clearance from cells. Various “molecular chaperones” have been identified that play an important role in escorting tau to its disposal systems.


Animal Models

Animal models of tauopathies allow us to study the impact of turning on and off different parts of the cellular pathway, seeing which steps play the most significant roles in disease. We also use model systems to test potential therapies, look for molecular changes at different stages, and measure tau levels. These model systems allow for rapid hypothesis testing around disease mechanisms. Complementary models in the same animal allow us to test the difference between naturally occurring normal (wild type) variations and disease-causing genetic variations.


Stem Cell Models

Patient-specific induced pluripotent stem cell (iPSC) models allow us to replicate a specific patient’s disease in cells in a petri dish, which allows us to study the molecular changes and processes that occur, as well as quickly and safely test potential drug treatments. iPSCs created in the Tau Consortium carry the rare A152T variant of the tau gene. Studying these cells with mass spectrometry allows the investigator to determine how much tau is produced and in what form. These cells can also be compared to other stem cells from someone with the same variant but no disease. The difference between the two people can illuminate any modifier effects of other genes or states (e.g., methylation, phosphorylation). iPSC models have already shown that the A152T variation increased tau fragmentation and phosphorylation, both toxic, while correcting the mutation removes the tauopathy.


Genomics

Whole-genome sequencing of large numbers of patients with progressive supranuclear palsy (PSP), A152T carriers worldwide, and healthy controls allows us to search for concurrent gene variations that either directly cause disease or impact the risk for developing PSP. Multidimensional analyses of genetic data allow us to identify genetic and epigenetic changes (e.g., methylation, phosphorylation) that may affect the risk for FTD spectrum disease.


Clinical & Biomarkers

As we prepare for clinical trials of potential therapies, we need to have accurate diagnoses to make sure the right people enter the clinical trials and that we have accurate measures of disease progression (e.g., protein levels in the blood or spinal fluid, imaging, pathogenic aggregates in cell culture medium). New techniques for measuring the health of specific networks of neurons in the brain have provided new insights to groups of patients. Now we want to know if the imaging can show the same changes occur in an individual as the disease progresses. Pathological studies of the brains of individuals carrying the A152T gene variation will allow us to determine how the genetic variation influences disease susceptibility. A clinical trial of a compound that improves microtubule function (important for cell structure), decreases abnormal tau, and improves thinking and movement is in the pipeline.


Drug Discovery

Our goal is to develop drugs that can be used to treat the tauopathies by decreasing levels of normal tau and by interfering with tau prion formation. Ideally, we may be able to develop cocktails of drugs—some of which lower normal tau, others that prevent conversion of tau into prions, and still others that enhance the clearance of tau prions (infectious proteins that can spread the disease from cell to cell in the brain).