Alphabeta hinders nuclear targeting of AICD and Fe65 in primary neuronal cultures.
The intracellular domain of the Alzheimer's amyloid precursor protein (AICD) has been described as an important player in the transactivation of specific genes. It results from proteolytic processing of the Alzheimer's amyloid precursor protein (APP), as does the neurotoxic Abeta peptide. Although normally produced in cells, Abeta is typically considered to be a neurotoxic peptide, causing devastating effects. By exposing primary neuronal cultures to relatively low Abeta concentrations, this peptide was shown to affect APP processing. Our findings indicate that APP C-terminal fragments are increased with concomitant reduction in the expression levels of APP itself. AICD nuclear immunoreactivity detected under control conditions was dramatically reduced in response to Abeta exposure. Additionally, intracellular protein levels of Fe65 and GSK3 were also decreased in response to Abeta. APP nuclear signaling is altered by Abeta, affecting not only AICD production but also its nuclear translocation and complex formation with Fe65. In effect, Abeta can trigger a physiological negative feedback mechanism that modulates its own production.
Henriques
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AG
Laboratório de Neurociências, Centro de Biologia Celular, SACS, Universidade de Aveiro, Campus de Santiago, Aveiro, Portugal.
Vieira
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SI
da Cruz e Silva
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EF
da Cruz e Silva
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OA