Downregulation of CREB expression in Alzheimer's brain and in A beta-treated rat hippocampal neurons

作者：Pugazhenthi, Subbiah^*; Wang, Maorong; Pham, Serena; Sze, Chun-I; Eckman, Christopher B.

来源：Molecular Neurodegeneration, 2011, 6(1): 60.

DOI：10.1186/1750-1326-6-60

• Alzheimer?'?s disease
• CREB
• Oxidative stress
• Apoptosis
• Tg2576 mice
• Laser capture microdissection

Background: Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and A beta. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post- mortem brain and in cultured rat hippocampal neurons exposed to A beta aggregates.
Results: Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS- extracted A beta and CREB protein levels in Alzheimer's post- mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to A beta fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in A beta-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against A beta-induced neuronal apoptosis.
Conclusions: Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.

• 出版日期2011-8-19
• 单位中国人民解放军第八一医院; 南京中医药大学