Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Dr. Michael Strong

Abstract

Cytoplasmic inclusions and fibrils of the microtubule-associated protein tau (tau protein) are a key neuropathological hallmark in tauopathies, including Alzheimer’s disease, chronic traumatic encephalopathy, and amyotrophic lateral sclerosis with cognitive impairment. Previous research has demonstrated that the phosphorylation of tau protein at Thr175 is sufficient for the initiation of fibril formation both in vitro and in vivo. Here we use mutated tau protein constructs to demonstrate that phosphorylation at Thr175 results in the aberrant exposure of an N-terminal phosphatase-activating domain (PAD). The tau PAD interacts with protein phosphatase 1 (PP1) leading to the activation of glycogen synthase kinase 3β (GSK3β), and subsequent fibril formation. Experimental rodent traumatic brain injury initiated the development of pThr175 tau fibrils in vivo, and associates with PAD exposure in the acute phases following injury. These data collectively suggest that pThr175 tau formation might initiate a pathological PAD-mediated neurotoxicity, resulting in the formation of tau fibrils.

Summary for Lay Audience

Traumatic brain injury (TBI) causes more disability amongst Canadians than any other neurological condition. In some instances, TBI can cause a molecule in the brain called tau to clump together. These clumps are called aggregates, and they can kill brain cells over time. Tau aggregates are found in numerous neurodegenerative conditions, including Alzheimer’s disease, chronic traumatic encephalopathy (CTE), and in amyotrophic lateral sclerosis (ALS/’Lou Gehrig’s disease’) with cognitive impairment (ALSci). Although it is well-established that tau aggregates are a feature of these conditions, the mechanisms by which TBI causes individual tau molecules to clump together are not well-understood. Our previous studies have shown that in these diseases, a specific part of tau has a phosphate group added onto it- specifically the threonine residue at position 175 on tau (termed ‘pThr175 tau’). This phosphate addition is only present in individuals with diseases, and we have shown previously that this specific modification contributes to tau aggregate formation. The goal of the current master’s thesis is to better understand how pThr175 tau leads to the formation of tau aggregates.

In the current thesis, I demonstrate that pThr175 tau has a different shape than tau without the phosphate group added. This change in shape causes tau to bind to and activate a series of other molecules in the cell which then add many phosphate molecules to tau, causing aggregation. I then show that the formation of tau aggregates could be reduced by making specific modifications to tau that prevent interactions with these other molecules. I then demonstrate that giving a TBI to a rat causes tau aggregates to form. Moreover, pThr175 tau forms early after a TBI, and is associated with a change in tau’s shape, just as in our previous experiments.

These studies collectively suggest that adding a phosphate group to Thr175 on tau changes the shape of tau and aberrantly activates other molecules. These other molecules then further modify tau and cause aggregates to form. Understanding this mechanism better allows us to identify specific changes to tau in the brain following TBI that may be stopped to prevent long-term disability in humans.

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