Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons

Abstract

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 alpha-1-antichymotrypsin (ACT). ACT has been shown to promote Abeta 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.

Plasma proteomic signature of age in healthy humans

“…SERPING1 modulates the complement cascade and is important in many inflammatory diseases, including macular degeneration (Ennis et al., 2008). SERPINA3 has been identified as a specific biomarker of delirium and Alzheimer's disease (Padmanabhan, Levy, Dickson, & Potter, 2006; Poljak et al., 2014). TIMP1 has been involved in age‐associated renal sclerotic and impairment kidney angiogenesis (Tan & Liu, 2012).…”

Complement activation as a biomarker for Alzheimer's disease

“…Acute-phase proteins including ␣1-antitrypsin, A2M, as well as C3, C4 and Factor P are also reported to be elevated in the serum of early onset AD cases when compared to controls (20 cases and 18 controls) suggesting that an increased amyloid burden is likely to be accompanied by an acute phase response (Giometto et al 1988). Increased peripheral ACT levels in APOE 4 positive patients also appear to predict an accelerated clinical progression (Padmanabhan et al 2006). Previous cross sectional studies also identified ACT elevated in AD plasma, along with inflammatory cytokines IL1, and IL6 (Licastro et al 2000).…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Activated astrocytes are mostly observed in areas with amyloid plaques (Nagele et al 2004). Effects of astrogliosis on accumulation of Ab are still debated, but Ab deposition (Mucke et al 2000;Nilsson et al 2001) and tau phosphorylation (Padmanabhan et al 2006) are enhanced by a1-antichymotrypsin, an acute-phase protein that is upregulated by activated astrocytes. Critical evidence for the role of astrogliosis in AD pathogenesis is the correlation between the extent of astrogliosis and cognitive impairment (Simpson et al 2010).…”