Characterization of the neurotrophic interaction between nerve growth factor and secreted alpha-amyloid precursor protein.
The expression and secretion of amyloid precursor protein (beta APP) is increased in rat cerebral cortices that have been denervated by subcortical lesions of the nucleus basalis of Meynert. The physiological role of the secreted beta APP in response to this injury has not been established. We have previously shown that secreted beta APP produced by alpha-secretase activity (sAPP(alpha)) potentiates the neuritogenic activity of nerve growth factor (NGF) in vitro on naive PC12 cells. In this investigation, we have further characterized the neurotrophic interaction of NGF and sAPP(alpha) using differentiated PC12 cells and rat primary cortical neurons. NGF required the expression of beta APP to maintain a neuronal phenotype. Reduction of endogenous beta APP expression by introduction of antisense oligonucleotides in the presence of NGF resulted in loss of neurites from differentiated PC12 cells but no apparent cell death. Addition of exogenous sAPP(alpha) (60--200 pM) potentiated the protective activity of NGF in serum-deprived differentiated PC12 cells as determined by retention of neurites and cell viability. In addition, exogenous sAPP(alpha) increased neuron viability in both short-term (3 days) cortical neuron cultures grown in the absence of serum and in long-term (9 days) cultures grown with serum. Disruption of the insulin signaling pathway by reduction of IRS-1 expression inhibited the ability of sAPP(alpha) to potentiate neurotrophic activity. These observations suggest that sAPP(alpha) acts as an injury-induced neurotrophic factor that interacts with NGF to enhance neuronal viability using the insulin signaling pathway.
Laboratory of Cellular and Molecular Biology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
J J
JJ
Luo
M S
MS
Wallace
D B
DB
Hawver
J W
JW
Kusiak
W C
WC
Wallace
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D020532:Basal Nucleus of Meynert / Q000293:injuries / Q000502:physiology*; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism*; D004396:Coloring Agents; D003470:Culture Media / Q000494:pharmacology; D004357:Drug Synergism; D010450:Endopeptidases / Q000494:pharmacology / Q000502:physiology; D005312:Fetal Blood; D005456:Fluorescent Dyes; D006133:Growth Substances / Q000097:blood / Q000494:pharmacology; D006736:Horses / Q000097:blood; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D009930:Organic Chemicals; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction
D016564:Amyloid beta-Protein Precursor; D004396:Coloring Agents; D003470:Culture Media; D005456:Fluorescent Dyes; D006133:Growth Substances; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D020319:Oligodeoxyribonucleotides, Antisense; D009930:Organic Chemicals; D010750:Phosphoproteins; C402795:SYTOX Green; D020932:Nerve Growth Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human