Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons.
The accumulation of beta-amyloid (Abeta) is one of the etiological factors in Alzheimer's disease (AD). It has been assumed that the underlying mechanism involves a critical role of Abeta-induced neurodegeneration. However, low levels of Abeta, such as will accumulate during the course of the disease, may interfere with neuronal function via mechanisms other than those involving neurodegeneration. We have been testing, therefore, the hypothesis that Abeta at levels insufficient to cause degeneration (sublethal) may interfere with critical signal transduction processes. In cultured cortical neurons Abeta at sublethal concentrations interferes with the brain-derived neurotrophic factor (BDNF)-induced activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. The effect of sublethal Abeta(1-42) on BDNF signaling results in the suppression of the activation of critical transcription factor cAMP response element-binding protein and Elk-1 and cAMP response element-mediated and serum response element-mediated transcription. The site of interference with the Ras/ERK and PI3-K/Akt signaling is downstream of the TrkB receptor and involves docking proteins insulin receptor substrate-1 and Shc, which convey receptor activation to the downstream effectors. The functional consequences of Abeta interference with signaling are robust, causing increased vulnerability of neurons, abrogating BDNF protection against DNA damage- and trophic deprivation-induced apoptosis. These new findings suggest that Abeta engenders a dysfunctional encoding state in neurons and may initiate and/or contribute to cognitive deficit at an early stage of AD before or along with neuronal degeneration.
Institute for Brain Aging and Dementia, University of California Irvine, Irvine, California 92697-4540, USA. tongl@uci.edu
Liqi
L
Tong
Robert
R
Balazs
Phillip L
PL
Thornton
Carl W
CW
Cotman
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020813:Receptor, trkB / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D010738:Type C Phospholipases / Q000502:physiology; D050807:ets-Domain Protein Elk-1
D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009419:Nerve Tissue Proteins; D015689:Oncogene Protein p21(ras); D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020813:Receptor, trkB; D014157:Transcription Factors; D010738:Type C Phospholipases; D050807:ets-Domain Protein Elk-1; C494114:Elk1 protein, rat; C075222:amyloid beta-protein (1-42); C494920:Akt1 protein, rat