The systemic amyloid precursor transthyretin (TTR) behaves as a neuronal stress protein regulated by HSF1 in SH-SY5Y human neuroblastoma cells and APP23 Alzheimer's disease model mice.
Increased neuronal synthesis of transthyretin (TTR) may favorably impact on Alzheimer's disease (AD) because TTR has been shown to inhibit Aβ aggregation and detoxify cell-damaging conformers. The mechanism whereby hippocampal and cortical neurons from AD patients and APP23 AD model mice produce more TTR is unknown. We now show that TTR expression in SH-SY5Y human neuroblastoma cells, primary hippocampal neurons and the hippocampus of APP23 mice, is significantly enhanced by heat shock factor 1 (HSF1). Chromatin immunoprecipitation (ChIP) assays demonstrated occupation of TTR promoter heat shock elements by HSF1 in APP23 hippocampi, primary murine hippocampal neurons, and SH-SY5Y cells, but not in mouse liver, cultured human hepatoma (HepG2) cells, or AC16 cultured human cardiomyocytes. Treating SH-SY5Y human neuroblastoma cells with heat shock or the HSF1 stimulator celastrol increased TTR transcription in parallel with that of HSP40, HSP70, and HSP90. With both treatments, ChIP showed increased occupancy of heat shock elements in the TTR promoter by HSF1. In vivo celastrol increased the HSF1 ChIP signal in hippocampus but not in liver. Transfection of a human HSF1 construct into SH-SY5Y cells increased TTR transcription and protein production, which could be blocked by shHSF1 antisense. The effect is neuron specific. In cultured HepG2 cells, HSF1 was either suppressive or had no effect on TTR expression confirming the differential effects of HSF1 on TTR transcription in different cell types.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and.
Xin
X
Wang
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Life Sciences, University of Siena, 53100 Siena, Italy.
Francesca
F
Cattaneo
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and.
Lisa
L
Ryno
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and.
John
J
Hulleman
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and.
Natàlia
N
Reixach
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and jbux@scripps.edu.
Joel N
JN
Buxbaum
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D011228:Prealbumin; D014157:Transcription Factors
Alzheimer's disease; HSF1; celastrol; heat shock; transgenics; transthyretin