All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Steven L Carroll

Lynn E Dobrunz

Emma Perez-Costas

Rosalinda C Roberts

J Michael Wyss

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Pathological hallmarks of AD include neurofibrillary tau tangles, amyloid beta (Abeta) accumulation and cholinergic degeneration. Cholinergic degeneration can be mimicked in rats by lesioning cholinergic neurons in medial septum. Hippocampal cholinergic denervation disrupts retrograde transport of nerve growth factor (NGF), leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Dr. McMahon's lab previously reported that coincident with this sprouting, there is an increase in cholinergic innervation that correlates with a recovery of M1 muscarinic receptor dependent plasticity at CA3-CA1 synapses and visual cortex. These findings suggest that noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. These beneficial effects of sprouting in rats prompted us to re-examine the presence of noradrenergic sympathetic sprouting in human hippocampus first reported by Booze et. al., 1993. Answering this question required the development of a new immunohistochemistry protocol, termed immunofluorochrome (IFC) staining. M1 mAChRs have been a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid beta-protein precursor (APP). Therefore, we next tested the hypothesis that noradrenergic sympathetic sprouting and the associated increase in cholinergic innervation maintains non-amyloidogenic APP processing that is dependent upon M1 mAChRs. Furthermore, we investigated if exogenous administration of NGF to hippocampus would stimulate noradrenergic sympathetic sprouting. Also, we investigated the effect of intrahippocampal Abeta42 infusion on noradrenergic sympathetic and cholinergic sprouting. Using our newly developed staining method, we concretely identified noradrenergic sympathetic sprouting in AD post-mortem human hippocampus. We also found that NGF stimulates sprouting and that sprouting maintains non-amyloidogenic APP processing. Furthermore, we showed that Abeta42 is not only toxic to central cholinergic fibers innervating hippocampus, but it prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target.

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