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 thatTTRexpression 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 ofTTRpromoter 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 increasedTTRtranscription in parallel with that ofHSP40,HSP70, andHSP90. With both treatments, ChIP showed increased occupancy of heat shock elements in theTTRpromoter by HSF1.In vivocelastrol increased the HSF1 ChIP signal in hippocampus but not in liver. Transfection of a humanHSF1construct into SH-SY5Y cells increasedTTRtranscription 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 onTTRtranscription in different cell types.