Brain Advance Access originally published online on September 20, 2006
Brain 2006 129(11):3020-3034; doi:10.1093/brain/awl255
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Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons
1 The Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute Jacksonville, FL, USA 2 Department of Molecular Medicine and Suncoast Gerentology Center, University of South Florida Jacksonville, FL, USA 3 Florida Alzheimer's Disease Research Center, Tampa Jacksonville, FL, USA 4 Neuropathology Laboratory, Mayo Clinic Jacksonville, FL, USA
Correspondence to: Jaya Padmanabhan, Department of Molecular Medicine, Room 2173, College of Medicine, USF, 12901 Bruce B. Downs Boulevard, Tampa, FL-33612, USA E-mail: jpadmana{at}health.usf.edu
Amyloid plaques and neurofibrillary tangles are key pathological features of Alzheimer's disease. Alzheimer's disease pathology is also characterized by neuroinflammation and neuronal degeneration, with the proteins associated with inflammatory responses being found in tight association with the plaques. One such protein is the serine protease inhibitor 
-1-antichymotrypsin (ACT). ACT has been shown to promote Aß polymerization in vitro and in vivo, and levels of ACT protein in plasma and cerebrospinal fluid from Alzheimer's patients have been found to correlate with progression of dementia. Here we investigated the possible involvement of ACT in tau phosphorylation and tangle formation. As was previously found for Alzheimer's disease, brains from patients with non-Alzheimer's tauopathies exhibited an enhanced expression of ACT, which correlated with the level of tau hyperphosphorylation. Transgenic mice expressing human ACT alone or ACT along with mutant human amyloid precursor protein (APP) showed a significant increase in tau phosphorylation, suggesting that this inflammatory protein can induce tau hyperphosphorylation. The increase in phosphorylation was observed at PHF-1 (P-Ser396/P-Thr404), P-Ser202 and P-Thr231 sites on tau, the P-tau epitopes that are associated with tangles in the patients. This result was further confirmed by the finding that addition of purified ACT induced the same Alzheimer's disease-related tau hyperphosphorylation in cortical neurons cultured in vitro. This correlated with an increase in extracellular signal regulated kinase (ERK) and glycogen synthase kinase-3 activation, indicating their involvement in ACT-induced tau phosphorylation. The ACT-treated neurons showed neurite loss and subsequently underwent apoptosis. Approximately 40–50% of neurons were TUNEL positive by 6 and at 24 h >70% of the neurons showed staining suggesting that ACT was inducing apoptosis in these neurons. These findings indicate that inappropriate inflammatory responses are a potential threat to the brain and that intervention directed at inhibiting the expression or function of ACT could be of therapeutic value in neurodegenerative diseases such as Alzheimer's and other tauopathies.
Key Words: alpha 1-antichymotrypsin; Alzheimer's disease; apoptosis; inflammation; neuron; phosphorylation; tau
Abbreviations:
AAT, 1-antitrypsin; ACT, 1-antichymotrypsin; ERK, early signal regulated kinase; GSK, glycogen synthase kinase; NFT, neurofibrillary tangle; PHF, paired helical filament
Received June 23, 2006. Revised August 19, 2006. Accepted August 21, 2006.