Date of Award
Honors College Thesis
Chemistry and Biochemistry
Alzheimer’s disease (AD) is the most common form of dementia affecting people over the age of 60, yet a detailed understanding of the molecular changes involved in AD remains a significant challenge to modern medicine. The hallmarks of an AD brain include the presence of senile plaques formed by a protein called amyloid-β (Aβ), along with inflammation of the brain. Aβ self-associates to form clumps of protein called “aggregates” which are known to be the primary toxic agents in AD pathology; however, several other proteins have also been implicated in this pathology. One such protein called progranulin (PGRN), which under normal physiological conditions plays a role in inflammation, has been shown to be present at higher concentrations in many neurodegenerative diseases including AD. The smaller fragments of PGRN are proinflammatory proteins known as granulins (Grn) that, interestingly, have a molecular structure similar to the one observed in Aβ aggregates. Due to this structural similarity and the colocalization of PGRN and Aβ in an AD brain we are investigating the interaction between the most common Grn, human Granulin-A (hGrn-A), and Aβ through several biochemical methods as well as the structure of hGrn-A itself. These studies have led to the discovery of a concentration-dependent change in conformational status of hGrn-A that we believe has an effect upon interactions with Aβ aggregates. Our results indicate that hGrn-A specifically interacts with Aβ in a concentration-dependent manner to effect both inhibition as well as augmentation of aggregate formation. This unique modulation of Aβ aggregate formation allows for an entirely new perspective on the mechanisms of AD pathology, though more trials are required to further characterize these interactions.
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Samel, Michael, "Exploring the Interaction Between Human Granulin-A (hGrn-A) and Amyloid-β (Aβ) Peptide" (2012). Honors Theses. 61.