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Date of Award

Spring 5-15-2018

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

Tauopathies are a diverse set of neurodegenerative diseases that feature the progressive accumulation of aggregated tau in the brain. Recent work suggests tau fibrils can propagate along neuronal networks and template the aggregation of natively folded tau protein ("seeding"). This prion-like spread is thought to underlie the progression of pathology observed in tauopathies. Prion diseases are caused by templated misfolding and assembly of prion protein into different amyloid conformations or strains. These distinct strains likely underlie the phenotypic diversity observed in human transmissible spongiform encephalopathies. During my dissertation, I tested whether tau can form unique prion strains that produce different pathological phenotypes in vivo. In collaborative work, we found that tau repeat domain can form different amyloid conformations that give rise to distinct morphological and biochemical phenotypes in culture. Inoculation of these strains into a tauopathy mouse model induced different patterns of histopathology that were stably propagated upon serial passage through three mouse generations. Aggregated tau from the final mouse generation retained the same conformations as the original strain inoculum, and induced identical cellular phenotypes after reintroduction into cell culture. I next showed tau strains can differentially target specific brain regions, and induce different rates of spread of tau pathology through the brain. To extend this work to human tauopathies, I developed an assay to quantify the level of seeding activity in fixed human tissue sections. I found that seeding activity progressively accumulates in Alzheimer's disease and progressive age-related tauopathy patients, beginning in the transentorhinal and entorhinal cortex before advancing to distant, anatomically connected brain regions. This work confirms tau can act as a true prion in vivo, and suggests different tau strains may underlie the progression of pathology and phenotypic diversity observed in human tauopathies.

Language

English (en)

Chair and Committee

Marc I. Diamond

Committee Members

David Holtzman, Jin-Moo Lee, Robert Mecham, Timothy Miller,

Comments

Permanent URL: https://doi.org/10.7936/K7M61JQ9

Available for download on Sunday, May 15, 2118

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