Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer’s Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation
The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer’s disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1β (IL-1β) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1β injection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD. 1. Introduction Alpha-1-antichymotrypsin (ACT), also called SERPINA3 [1], is a member of the serine protease inhibitor (serpin) family of acute phase proteins. Although ACT is predominantly produced in the liver, it is also synthesized in the brain, mainly by astrocytes [2]. Elevated levels of ACT are found in the brain [3, 4], serum and cerebrospinal fluid (CSF) [5] of AD patients, and high levels of ACT in plasma is associated with cognitive decline in elderly subjects [6]. This suggests that ACT may serve as a biomarker for early diagnosis of the disease. Studies in transgenic mouse models of AD have shown that expression of a human ACT gene accelerates amyloid plaque formation [7, 8] and cognitive decline [9] confirming the role of ACT in AD pathophysiology. The data from in vitro studies suggest that ACT binds Aβ peptide and affects the rate of amyloid fibril formation [10–13], possibly causing the accelerated Aβ aggregation and plaque formation observed in vivo. Various cytokines and growth factors such as interleukin 1 (IL-1), IL-6, tumor necrosis factor alpha (TNFα), oncostatin M, and leukemia inhibitory factor have been shown to regulate expression of acute phase
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