Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of A?PP.

ABSTRACT: Alzheimer's disease (AD) is characterized by amyloid-? (A?) 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-? protein precursor (A?PP). Here we tested the hypotheses that noradrenergic sympathetic sprouting is triggered by NGF, that sprouting maintains non-amyloidogenic A?PP processing, and that sprouting is prevented by intrahippocampal A?42 infusion. We found that NGF stimulates sprouting, that sprouting maintains non-amyloidogenic A?PP processing, and that A?42 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.

SUBMITTER: Nelson AR 

PROVIDER: S-EPMC4047988 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature