Affiliations: [a] Division of Endocrinology, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA | [b] Division of Neuroscience, Department of Pathology, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA
Correspondence:
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Corresponding author: Dr. LuGuang Luo, Division of Endocrinology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. Tel.: +1 401 444 8578; Fax: +1 401 444 4921; E-mail: Lu-Guang_Luo@Brown.edu.
Abstract: Thyrotropin-releasing hormone (TRH) is best known for its hypothalamic neuroendocrine role in regulating thyroid function. In extra-hypothalamic regions in vitro, we have shown TRH to have a protective effect against synaptic loss and neuronal apoptosis. A role for TRH in Alzheimer's disease (AD) has not been established previously. In this study, we examined the content of the TRH peptide in the hippocampus of elderly controls (n=5) and AD patients (n=7) by radioimmunoassay (RIA). The TRH concentration was decreased in the AD hippocampus compared to normal elderly controls (p > 0.01). In a separate series of experiments utilizing primary cell cultures made from rat hippocampus, TRH peptide concentration was depleted by the addition of TRH antiserum. TRH withdrawal was found to enhance the activity of glycogen synthetase kinase-3 (GSK-3β), a critical enzyme necessary for the phosphorylation of tau, as well as the phosphorylation of the tau protein itself. This TRH depletion induced upregulation in phosphorylation that was observed to initiate axonal retraction in cultured neurons. These data suggest that TRH within the hippocampus can regulate the activity of various proteins by phosphorylation/dephosphorylation that may be involved in the pathogenesis of AD.
