Date of Award

1-1-2018

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

Chemistry and Biochemistry

First Advisor

Martin Margittai, Ph.D.

Second Advisor

Michelle Knowles

Third Advisor

J. Alex Huffman

Fourth Advisor

Joseph Angleson

Keywords

Alzheimer's Disease, Fibril, MAP2, Microtubule associated protein 2, Tau

Abstract

Tau fibrils are a pathological hallmark of over 20 neurodegenerative disorders, including Alzheimer's disease. There currently is no cure for these diseases and treatments are limited. Once Tau fibrils form in the brain, they propagate down neuronal networks, and this spreading is linked to disease progression. Studying the behavior and structure of Tau monomer and Tau aggregates therefore may give insight into methods by which the spread of Tau fibrils can be inhibited. The structures of the Tau fibrils from different diseases are thought to vary, partially giving rise to the different disease phenotypes. Tau natively binds to microtubules by either three or four imperfect repeat regions, giving rise to the naming convention of 3R and 4R Tau. In solution, full-length Tau exists as a disordered monomer in dynamic conformational equilibrium. This solution-phase heterogeneity could, in part, explain conformational diversity of Tau fibrils.

A homogeneous set of Tau fibrils transitioned to a new heterogeneous population of conformers after multiple cycles of seeding. The original fibrils were formed under stirring conditions, which enhanced the fragile population. Under the quiescent growth conditions of multiple cycles of seeding, the faster growing populations became the dominant set of conformers. This explains how a new dominant fibril population can evolve from minor subpopulations. These findings demonstrate that changes in the selective pressures on Tau fibrils during fibril propagation could lead to the formation of polymorphs with differing clinical consequences.

Microtubule associated protein 2 (MAP2) is a neuronal homologue to Tau and performs similar functions in the cell. MAP2 has not been shown to be a major antigenic component of the neurofibrillary tangles associated with disease. However, this does not exclude their presence in small quantities. Microtubule binding repeat regions from 3R and 4R MAP2 slow nucleation and block seeded aggregation of 4R Tau protein. Also, as few as a single MAP2 molecule bind to and cap the 4R Tau fibril end. This could account for the inhibition via disruption of the ability of Tau to subsequently bind to the capped fibril end. MAP2 inhibition of Tau fibril formation and progression could be a natural modulator of the fibril spreading in the brain.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Michael R. Holden

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

149 p.

Discipline

Biochemistry, Neurosciences

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