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Date of Award

Winter 12-15-2017

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

Brain extracellular concentration of the peptide amyloid-β (Aβ) is a major contributor to Alzheimer’s disease (AD) pathogenesis. High Aβ levels in the extracellular space precipitate aggregation of the peptide into soluble and insoluble toxic species. This process begins decades before cognitive impairment and triggers the cascade of pathology that eventually leads to AD. Synaptic activity is key to the regulation of extracellular Aβ levels. Presynaptic activity drives the production of Aβ, while postsynaptic receptor activation exhibits more nuanced regulation. For example, high levels of NMDA receptor (NMDA-R) activation have been shown to decrease Aβ production through the extracellular signal-regulated kinase (ERK). The studies outlined in this document sought to determine the pathways by which Aβ levels are influenced by NMDA-Rs as well as the other major ionotropic glutamate receptors, AMPA-Rs. We found that NMDA-Rs activate ERK and decrease Aβ production through a pathway non-specific to NMDA-R subtype or ERK isoform and that does not rely on calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), or protein kinase C (PKC) signaling. We also found that though basal AMPA-R activity increases Aβ levels, evoked activation of AMPA-Rs reduces extracellular Aβ through distinct NMDA-R-dependent and independent pathways. Unexpectedly, NMDA-R-independent AMPA-R regulation decreases Aβ levels by reducing its half-life in the extracellular fluid. Because previous studies describe synaptic activity-mediated Aβ regulation through altered production, this finding presents a novel link between synaptic transmission and Aβ clearance. The work described here aims to explore the mechanisms by which normal brain activity influences Aβ homeostasis in an effort to more fully understand AD pathogenesis.

Language

English (en)

Chair and Committee

John R. Cirrito

Committee Members

Steven Mennerick, Jin Moo Lee, Erik Musiek, Karen O'Malley,

Comments

Permanent URL: https://doi.org/10.7936/K7JQ10FN

Available for download on Sunday, December 15, 2019

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