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Interactions of cholinergic innervation and soluble Aβ42 peptide metabolism in the hippocampus

Isanski, Barbara Anna (2007) Interactions of cholinergic innervation and soluble Aβ42 peptide metabolism in the hippocampus. Master's Thesis, University of Pittsburgh. (Unpublished)

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Alzheimer's 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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Isanski, Barbara
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCard, Patrickcard@pitt.eduCARD
Committee MemberDeKosky, Steven
Committee MemberHastings, Teresahastings@bns.pitt.eduTHASTING
Date: 19 December 2007
Date Type: Completion
Defense Date: 14 December 2007
Approval Date: 19 December 2007
Submission Date: 19 December 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Alzheimer's Disease; amyloid-β; fimbria fornix lesion
Other ID:, etd-12192007-000351
Date Deposited: 10 Nov 2011 20:11
Last Modified: 15 Nov 2016 13:54


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