PMID- 15282285 OWN - NLM STAT- MEDLINE DCOM- 20050215 LR - 20211203 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 24 IP - 30 DP - 2004 Jul 28 TI - Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. PG - 6799-809 AB - 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. FAU - Tong, Liqi AU - Tong L AD - Institute for Brain Aging and Dementia, University of California Irvine, Irvine, California 92697-4540, USA. tongl@uci.edu FAU - Balazs, Robert AU - Balazs R FAU - Thornton, Phillip L AU - Thornton PL FAU - Cotman, Carl W AU - Cotman CW LA - eng GR - R01 NS040953/NS/NINDS NIH HHS/United States GR - R01-NS040953/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Amyloid beta-Peptides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (DNA-Binding Proteins) RN - 0 (Elk1 protein, rat) RN - 0 (Nerve Tissue Proteins) RN - 0 (Peptide Fragments) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Transcription Factors) RN - 0 (amyloid beta-protein (1-42)) RN - 0 (ets-Domain Protein Elk-1) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.1 (Akt1 protein, rat) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 3.1.4.- (Type C Phospholipases) RN - EC 3.1.4.3 (Phospholipase C gamma) RN - EC 3.6.5.2 (Oncogene Protein p21(ras)) SB - IM MH - Alzheimer Disease/etiology/metabolism MH - Amyloid beta-Peptides/administration & dosage/chemical synthesis/*pharmacology MH - Animals MH - Brain-Derived Neurotrophic Factor/*antagonists & inhibitors/pharmacology MH - Cells, Cultured/drug effects/physiology MH - Cerebral Cortex/*cytology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - DNA-Binding Proteins/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Activation/drug effects MH - Extracellular Signal-Regulated MAP Kinases/physiology MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - MAP Kinase Signaling System/drug effects MH - Nerve Tissue Proteins/*physiology MH - Neurons/*drug effects/physiology MH - Oncogene Protein p21(ras)/physiology MH - Peptide Fragments/administration & dosage/chemical synthesis/*pharmacology MH - Phosphatidylinositol 3-Kinases/physiology MH - Phospholipase C gamma MH - Phosphorylation MH - Protein Processing, Post-Translational MH - Protein Serine-Threonine Kinases/physiology MH - Proto-Oncogene Proteins/metabolism/physiology MH - Proto-Oncogene Proteins c-akt MH - Rats MH - Receptor, trkB/physiology MH - Signal Transduction/*drug effects MH - Transcription Factors/metabolism MH - Transfection MH - Type C Phospholipases/physiology MH - ets-Domain Protein Elk-1 PMC - PMC6729714 EDAT- 2004/07/30 05:00 MHDA- 2005/02/16 09:00 PMCR- 2005/01/28 CRDT- 2004/07/30 05:00 PHST- 2004/07/30 05:00 [pubmed] PHST- 2005/02/16 09:00 [medline] PHST- 2004/07/30 05:00 [entrez] PHST- 2005/01/28 00:00 [pmc-release] AID - 24/30/6799 [pii] AID - 10.1523/JNEUROSCI.5463-03.2004 [doi] PST - ppublish SO - J Neurosci. 2004 Jul 28;24(30):6799-809. doi: 10.1523/JNEUROSCI.5463-03.2004.