Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of AβPP

Academic Article

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. © 2014 - IOS Press and the authors. All rights reserved.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Nelson AR; Kolasa K; McMahon LL
  • Start Page

  • 867
  • End Page

  • 879
  • Volume

  • 38
  • Issue

  • 4