Advisory Committee Chair
Lori L McMahon
Advisory Committee Members
Karen Gamble
Qin Wang
Document Type
Thesis
Date of Award
2020
Degree Name by School
Master of Science (MS) Heersink School of Medicine
Abstract
Locus coeruleus (LC) degeneration in Alzheimer’s Disease (AD) and loss of noradrenergic (NA) innervation in hippocampus contributes to learning and memory deficits. Recently, a novel rat model (TgF344-AD) has been created that allows for a more thorough investigation into these mechanisms due to its similarity to human AD pathology. The McMahon lab has recently demonstrated heightened long-term potentiation (LTP) and a ‘supersensitivity’ of -adrenergic receptors (-ARs) at excitatory synapses in the dentate gyrus (DG) in TgF344-AD rats. These mechanisms could be responsible for maintaining learning and memory during buildup of AD pathology. The first goal of this Master’s thesis was to test the hypothesis that downstream targets of β-ARs are heightened in TgF344-AD rats following activation using isoproterenol (ISO), a β-AR agonist, using 9-10 month old male and female rats to focus on the prodromal phase of AD. Western blotting was used to quantify phosphorylated extracellular signal regulated kinase (pERK) and serine845 subunits on GluA1 subunits, and an enzyme activity kit was used to measure protein kinase A (PKA) in DG and area CA1. In DG, but not CA1, pERK 44 was significantly increased in TgF344 compared to WT, and no differences were found in PKA activity. pSer845 GluA1 was increased similarly in both TgF344-AD and WT rats. A second goal was to test the hypothesis that TgF344-AD rats rely more heavily on β-ARs in hippocampus-dependent learning and memory compared to WT rats. The β-AR antagonist propranolol (PROP) was bilaterally infused into the lateral ventricle to test whether a behavioral deficit is unmasked in TgF344-AD rats in novel object recognition (NOR) and fear conditioning (FC) tasks. Data show that β-ARs are needed for extinction learning in TgF344-AD rats but not in WT rats, and that TgF344-AD rats have an advantage in NOR over WT that required -ARs. Collectively, these findings establish that β-ARs have heightened pERK signaling during prodromal AD and that -ARs maintaining extinction learning and provides an advantage in NOR. These findings also establish the utility of this preclinical model in understanding how the NA system can be targeted for therapeutic benefit in AD pathology.
Recommended Citation
Langner, Bethany, "Locus Coeruleus Degeneration In Alzheimer’S Disease And Its Effect On Beta-Adrenergic Signaling In The Hippocampus" (2020). All ETDs from UAB. 674.
https://digitalcommons.library.uab.edu/etd-collection/674