ProNGF inhibits NGF-mediated TrkA activation in PC12 cells.
Degeneration of cholinergic basal forebrain neurons (CBFN) is a hallmark in the pathology of Alzheimer's disease (AD). Critically depending upon the neurotrophic support through nerve growth factor (NGF), CBFN in the AD brain face elevated concentrations of the pro-form of NGF (proNGF) and suffer from an imbalance between TrkA and p75(NTR) expression. Research for the underlying mechanisms of CBFN death suggested a pro-apoptotic activity of proNGF. However, this finding could not be confirmed by all investigators and other studies even observed a neurotrophic function of proNGF. In the presence of these controversial findings we investigated the activity of proNGF in PC12 cells with specific emphasis on its neurotoxic versus neurotrophic action. In this study, we show that proNGF can mediate TrkA receptor signaling directly, yet in the manner of a partial agonist with a lower maximum activity than NGF. A pro-apoptotic activity of proNGF could not be confirmed in our cellular system. Interestingly and surprisingly, pre-incubation with proNGF at low, sub-active concentrations inhibited TrkA-mediated neurotrophic NGF signaling in PC12 cells. Our data support a novel hypothesis for the role of elevated proNGF levels in CBFN pathology in AD. Thus, proNGF can indirectly contribute to the slow neurodegeneration in AD by reducing NGF-mediated trophic support.
Sobottka
Bettina
B
F. Hoffmann-La Roche Ltd., CNS Preclinical Research, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Reinhardt
Dieter
D
Brockhaus
Manfred
M
Jacobsen
Helmut
H
Metzger
Friedrich
F
D000818:Animals; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection / Q000379:methods
D009414:Nerve Growth Factors; D011498:Protein Precursors; C514218:pro-nerve growth factor, rat; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases