| Alzheimer's disease (AD) is characterized by cognitive dysfunction and neuronal loss, believed to be due to excess amyloid-beta peptide (Abeta). The prevailing hypothesis is that Abeta reduces cAMP response element binding protein (CREB) phosphorylation and impairs its signaling, leading to synaptic dysfunction and neuronal degeneration. However, this hypothesis has not been examined in AD. Here, we report that there is no significant change in CREB phosphorylation status in a familial Alzheimer's mouse model (TgCRND8) and AD brain, relative to Non-Tg (C3H/C57 genetic background mouse) and Non-AD (patients who did not die of neurological diseases), respectively. Surprisingly, CREB is expressed predominantly in cytoplasm of the TgCRND8 mice and AD brain cells, in contrast to their nuclear localization in controls. Consistently, CREB-DNA binding activity and cAMP response element (CRE) dependent transcription is suppressed in primary cortical neuronal cultures from the TgCRND8 mice, indicating impairment in CREB signaling. Coimmunoprecipitation identifies a novel interaction between the carboxy-terminal fragment (CTF) of amyloid precursor protein (APP-CTF100) and CREB, leading to cytosolic anchorment of CREB and inhibition of its nuclear translocation. This interaction is significantly (P<0.05) higher in the TgCRND8 mice and AD brain compared to controls. Although CREB overexpression results in its nuclear accumulation and reduction in Abeta-induced neurotoxicity, there is no significant difference between this neuroprotective activity of CREB and phospho-CREBSer133. Co-expression of N-but not C-terminal deletion APP mutant and CREB, leads to a marked reduction in nuclear CREB levels and increased Abeta-induced neurotoxicity. Furthermore, it has been shown a significant increase of cell apoptosis in the TgCRND8 mice and AD brains, compared with Non-Tg mice and Non-AD brains. Apoptotic cells in TgCRND8 mice and AD brains express markedly reduced nuclear CREB levels. These new findings suggest that reduction in nuclear CREB, but not phospho-CREB levels could sensitize neurons to Abeta-toxicity, and likely contributes to neurodegeneration in AD. |
