Amyloid beta serves as an NGF-like neurotrophic factor or acts as a NGF antagonist depending on its concentration.
In the nervous system, both the shape and connectivity of neurons are strongly influenced by soluble, extracellular factors. Indeed, we recently demonstrated that after binding to p75(NTR), the common neurotrophin receptor, nerve growth factor (NGF) controls the morphology and connectivity of cultured mouse hippocampal neurons by encouraging the production of fewer yet longer dendrites, and by augmenting GABAergic connectivity. These effects of NGF are mediated by the differential expression of Enhancer-of-split 1/5 homologs and neurogenin 3. Amyloid beta (Abeta), a pathogenic agent in Alzheimer's disease (AD) is known to bind to p75(NTR), hence we studied its influence on cultured hippocampal neurons. At 800 nM, Abeta(1-40) prevents NGF-induced activation of NF-kappaB and consequently, it depresses the expression of Enhancer-of-split 1. Thus, at this concentration, the effect of Abeta on neurons is antagonistic to those provoked by NGF and accordingly, neurons sprout more yet shorter dendrites and their GABAergic input decreases. In contrast, at lower concentration, 20 nM, the amyloid induces cellular effects similar to those induced by NGF, both in terms of gene expression, neuronal morphology, and GABAergic connectivity. Our results demonstrate that Abeta may act as a neurotrophic factor that mimics the activity of NGF. However, at higher concentrations, the amyloid behaves as an antagonist of NGF, contributing to the advent of AD.
Arevalo
Maria-Angeles
MA
Instituto Cajal de Neurobiología, CSIC, Madrid, Spain.
Roldan
Pedro M
PM
Chacón
Pedro J
PJ
Rodríguez-Tebar
Alfredo
A
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D020672:I-kappa B Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection / Q000379:methods; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D020672:I-kappa B Proteins; D016328:NF-kappa B; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor