Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Article type: Research Article
Authors: Nelson, Amy R. | Kolasa, Krystyna | McMahon, Lori L.; *
Affiliations: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Correspondence: [*] Correspondence to: Lori L. McMahon, PhD, Jarman F. Lowder Professor of Neuroscience, Director, Comprehensive Neuroscience Center, Associate Director, Center for Aging, President, Birmingham Chapter of the Society for Neuroscience, Department of Cell, Developmental, and Integrative Biology, UAB, 1918 University Blvd MCLM 808, Birmingham, AL 35294-0005, USA. Tel.: +1 205 934 3523; Fax: +1 205 975 9028; E-mail: [email protected].
Abstract: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, hyperphosphorylated tau neurofibrillary tangles, and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning medial septum cholinergic neurons. Hippocampal cholinergic denervation disrupts retrograde nerve growth factor (NGF) transport, leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers and the maintenance of a M1 muscarinic acetylcholine receptor (M1 mAChR) dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Importantly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in human postmortem AD hippocampus. Furthermore, M1 mAChRs are a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid-β protein precursor (AβPP). Here we tested the hypotheses that noradrenergic sympathetic sprouting is triggered by NGF, that sprouting maintains non-amyloidogenic AβPP processing, and that sprouting is prevented by intrahippocampal Aβ42 infusion. We found that NGF stimulates sprouting, that sprouting maintains non-amyloidogenic AβPP processing, and that Aβ42 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.
Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cholinergic fibers, muscarinic receptor M1, nerve growth factor
DOI: 10.3233/JAD-130608
Journal: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 867-879, 2014
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
[email protected]
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]