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However, low levels of A\u03b2, 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 A\u03b2 at levels insufficient to cause degeneration (sublethal) may interfere with critical signal transduction processes. In cultured cortical neurons A\u03b2 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 A\u03b2<jats:sub>1-42<\/jats:sub>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 A\u03b2 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 A\u03b2 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.<\/jats:p>","DOI":"10.1523\/jneurosci.5463-03.2004","type":"journal-article","created":{"date-parts":[[2004,7,28]],"date-time":"2004-07-28T19:57:48Z","timestamp":1091044668000},"page":"6799-6809","source":"Crossref","is-referenced-by-count":196,"title":["\u03b2-Amyloid Peptide at Sublethal Concentrations Downregulates Brain-Derived Neurotrophic Factor Functions in Cultured Cortical Neurons"],"prefix":"10.1523","volume":"24","author":[{"given":"Liqi","family":"Tong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Balazs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip L.","family":"Thornton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl W.","family":"Cotman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2004,7,28]]},"reference":[{"key":"2023041303074596000_24.30.6799.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01415-4"},{"key":"2023041303074596000_24.30.6799.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(97)00050-7"},{"key":"2023041303074596000_24.30.6799.3","doi-asserted-by":"publisher","DOI":"10.1038\/2836"},{"key":"2023041303074596000_24.30.6799.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5443.1358"},{"key":"2023041303074596000_24.30.6799.5","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90400-6"},{"key":"2023041303074596000_24.30.6799.6","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/S0021-9258(18)48529-8","volume":"267","year":"1992","journal-title":"J Biol Chem"},{"key":"2023041303074596000_24.30.6799.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80266-4"},{"key":"2023041303074596000_24.30.6799.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003390200"},{"key":"2023041303074596000_24.30.6799.9","doi-asserted-by":"publisher","DOI":"10.1038\/6374"},{"key":"2023041303074596000_24.30.6799.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(97)00125-3"},{"key":"2023041303074596000_24.30.6799.11","unstructured":"Cotman CW, Ivins KJ, Anderson AJ (1999) Apoptosis in Alzheimer disease. 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