ORCID

http://orcid.org/0000-0003-4048-2107

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The microtubule associated protein tau (MAPT, commonly referred to as tau) is an intrinsically disordered, highly soluble protein predominantly expressed in axons where it binds and stabilizes microtubules. Under normal physiological conditions, soluble monomeric tau is released in the extracellular space in the interstitial fluid (ISF) by neurons. Additionally it undergoes reversible phosphorylation and other extensive modifications inside the cell under the action of a host of enzymes. However in the disease process tau loses this solubility, detaches from microtubules and ultimately migrates to the somatodendritic compartment of the neuron, where it ultimately forms insoluble fibrillar aggregates known as tau tangles. The nature, timeframe, and inciting factors of this transformation are active areas of research and as such, remain only partially understood. In addition to its role in AD, tau is also implicated in several other neurodegenerative conditions collectively referred to as tauopathies, all of which feature insoluble tau tangles. This list, which is still evolving, includes conditions such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), and argyrophilic grain disease (AGD). The prevailing hypothesis about the pathogenesis of tauopathies is that following an initiating event, intracellular tau aggregates and eventually spreads to other parts of the brain where it seeds previously normal tau, in a prion-like manner. These seeding and spreading phenomena have been observed in numerous mouse models. The nature of tau species involved in this spread, as well as the exact mechanism of trans-synaptic spread are not well understood. Tauճ involvement in neurodegeneration has made it an attractive therapeutic target. Passive immunotherapy with monoclonal antibodies has shown promise and is being tested in clinical trials in humans. Vaccination trials are also underway. In addition, other approaches such as antisense oligonucleotides (ASOs) and small molecule inhibitors have been tested in animal models. Here we have mainly focused on three distinct but related aspects in the Ҭife of tau:Ӽ/p>1. Developing methods to measure tau oligomers2. Determining clearance kinetics of extracellular tau from the CNS to the periphery3. Evaluating plasma tau as a potential biomarker for CNS tau pathologyTau oligomers are thought to be an important intermediate step en route to the eventual fibrillization of soluble monomeric tau. We developed a high-sensitivity assay on a single molecule detection platform to detect tau oligomers. Our work characterizing extracellular tau clearance is the first comprehensive work of its type and strongly suggests that dural lymphatic system plays a key role in this process. Mice lacking these lymph vessels retain more tau in the brain as well as show slowed clearance. Lastly we asked whether plasma tau could serve as a reliable biomarker for soluble CNS tau and give us an accurate snapshot of tau pathology. Administration of an anti-tau antibody resulted in dose dependent increase in plasma tau in both humans and mice, most likely because of its role in extending the half-life of plasma tau from 8 minutes to 3 hours. Furthermore plasma tau levels correlated with soluble CNS tau levels (and therefore, inversely with tau pathology), making this a potentially good strategy to monitor tau pathology load in mouse model of tauopathy and potentially in humans. The work done here represents an important step in characterizing the role of tau in normal physiology and disease and will help guide future therapy as well as diagnostic approaches.

Language

English (en)

Chair and Committee

David M. Holtzman

Committee Members

Erik Musiek, Paul Kotzbauer, Celeste Karch, Timothy Miller,

Download

Share

COinS