Author

Kelly G. Hill

Date of Award

5-2017

Degree Type

Honors College Thesis

Department

Chemistry and Biochemistry

First Advisor

Vijay Rangachari, Ph.D.

Advisor Department

Chemistry and Biochemistry

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by extensive memory loss and cognitive deficits, which occur due to severe neuronal loss. Two hallmark lesions, intracellular neurofibrillary tangles composed of hyperphosphorylated tau and extracellular neuritic plaques formed by the aggregation of amyloid-β (Aβ), are responsible for the progressive neuronal loss seen in AD brains. Neurotoxic Aβ aggregates are also known to cause inflammation within the brain. It has recently come to light that severe and acute inflammation, such as seen in traumatic brain injury (TBI), may also lead to AD-type dementia. This has raised the question whether some of the pro-inflammatory mediators released from activated microglial cells could play a role in promoting the aggregation of Aβ and subsequent plaque formation. We hypothesize that a small family of cysteine rich, pro-inflammatory proteins called Granulins (Grns), which have been implicated in both AD and frontotemporal dementia (FTD), modulate Aβ aggregation. Based on the data obtained in our lab on GRN-3 protein, we have focused on P43LGRN-3, a missense mutant of GRN-3, which has been implicated in pathology. P43LGRN-3 was recombinantly expressed in E. coli, purified, and characterized by biochemical and biophysical tools. The effect of P43LGRN-3 on the binding and aggregation of Aβ was investigated via co-incubation experiments. The collected data suggest that monomeric P43LGRN-3 is largely similar to wild type GRN-3 (wt-GRN3) both structurally and functionally, and suggests the possible differences between the mutant and the wild-type protein could be more prominent with the precursor protein, progranulin. These data are presented and discussed.

Included in

Biochemistry Commons

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