Revisiting the cholinergic hypothesis in the development of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population today; however, there is currently no accurate description of the etiology of this devastating disorder. No single factor theory has been demonstrated as being causative; however, an alternative theory suggests that the interaction of multiple risk factors is responsible for AD. In this thesis I present data suggesting a neuroprotective role for acetylcholine during aging. Using a rat model of cholinergic depletion of the medial septum, I explored the effects of four common risk factors for AD (stress, seizures, stroke and circadian dysfunction) targeted at the hippocampus and examined the effects on measures of hippocampal dependent (water maze) and hippocampal independent (fear conditioning) memory. Here, I propose a role for acetylcholinemediated compensatory mechanisms in the functional recovery observed following sub threshold insults similar to those commonly observed in the elderly. m First and foremost I would like to thank my supervisor, Dr. Robert McDonald. Thank you for your support and encouragement, and for allowing me the independence to pursue my own projects and to learn from my experiences. I would also like to thank Nhung Hong for doing the majority of the cholinergic depletion and stroke surgeries used in this thesis and for teaching me the techniques. I would like to give a huge thank you to Joelle Kopp who was an invaluable asset who assisted in histology and spent many hours on the microscope counting cholinergic neurons. I would also like to thank Dr. Christine Werk for patiently reading and re-reading early drafts of my papers and this thesis and Dr.Hugo Lehmann for all his help in running statistics and interpreting my data. In addition, many thanks go out to Courtney Lamb, Robert Court and Arthur Verhoef for helping me with histology and behavioural testing, to Keri Colwell for running the corticosterone assays, the Metz lab for kindly allowing me the use of their microscope and to Karen Dow-Cazel and the rest of the animal care staff for taking care of my rats and helping me set up the circadian experiements. The cholinergic hypothesis of Alzheimer's disease 6 Acknowledgements IVThe basal forebrain cholinergic system 8The role of the basal forebrain cholinergic system in learning and memory 10The current state of the cholinergic hypothesis of Alzhimer's disease 15Risk factors for Alzheimer's disease 16Multiple combinations of co-factors theory of Alzheimer's disease 22The role of the hippocampus in learning and memory 24Objective of the present thesis 25Chapter 2: A series of pilot studies to determine the threshold for behaviourally sub threshold stroke, seizures and stress 28Abstract 29Experiment la: The effect of a chronic variable stress schedule on performance of the water maze task 32 Materials and Methods 33Results 36Experiment lb: The effects of a variable restraint stress procedure on levels of blood borne CORT 39 Materials and Methods 39Results 40Discussion 41Experiment 2: T...

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