Alzheimers Disease (AD) is a chronic neurodegenerative disorder characterized clinically by dementia and neuropathologically by the presence of amyloid-β (Aβ) plaques, neurofibrillary tangles, and neuronal and synapse loss. AD dementia severity correlates with reductions in synapses as well as in cholinergic markers, including choline acetyltransferase (ChAT) and acetylcholine esterase (AChE). However, the exact relationship of these changes with Aβ metabolism and plaques is unclear. Recently, it has been proposed that reduced cholinergic activity can increase levels of Aβ peptide. We investigated this relationship using a well-characterized model of hippocampal cholinergic denervation (achieved by fimbria-fornix transection) in a unique human Aβ "knock-in" mouse model of AD. The fimbria fornix lesion was effective in diminishing the cholinergic input to the hippocampus; ChAT immunoreactive fiber densities were reduced in the hippocampus, and cholinergic enzyme activity levels were reduced by almost 50% compared to naïve animals. Fimbria fornix lesions also resulted in a 3-fold increase in soluble Aβ42 over naives, supporting the hypothesis that loss of cholinergic innervation increases Aβ peptide levels in target fields. Our data indicate that cholinomimetic therapies could prove valuable in suppressing increases in potentially neurotoxic soluble Aβ levels, and provide a model for evaluating in vivo the relationship between cholinergic function and amyloid metabolism.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12192007-000351 |
| Date | 19 December 2007 |
| Creators | Isanski, Barbara Anna |
| Contributors | Teresa Hastings, PhD, Steven T. DeKosky, MD, Patrick Card, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12192007-000351/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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