Anticancer Activity and Mechanisms of Action of MAPK pathway inhibitors


2012;73:1204C1215. in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. INTRODUCTION Tau is usually a microtubule-associated protein that forms intracellular aggregates in several neurodegenerative diseases collectively termed tauopathies. These include Alzheimer’s disease (AD), progressive supranculear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia (FTD) (Mandelkow and Mandelkow, 2012). Tau is usually a highly soluble and natively unfolded protein (Jeganathan et al., 2008) which binds and promotes the assembly of microtubules (Drechsel et al., 1992; Witman et al., 1976). In tauopathies, (-)-Catechin gallate tau accumulates in hyperphosphorylated neurofibrillary tangles (NFTs) that are visualized within dystrophic neurites and cell body (Mandelkow and Mandelkow, 2012). The amount of tau pathology correlates with progressive neuronal dysfunction, synaptic loss, and functional decline in humans and transgenic mouse models (Arriagada et al., 1992; Bancher et al., 1993; Polydoro et al., (-)-Catechin gallate 2009; Small and Duff, 2008). In human tauopathies, pathology progresses from one brain region to another in disease-specific patterns (Braak and Braak, 1997; Raj et al., 2012; Seeley et al., 2009; Zhou et al., 2012), even though underlying mechanism is not yet obvious. The prion hypothesis holds that tau aggregates escape cells of origin to enter adjacent cells, where they seed further tau aggregation and propagate pathology (Frost and Diamond, 2010). We have previously observed that recombinant tau fibrils will induce aggregation of full-length intracellular tau in cultured cells, and that aggregated forms of tau transfer between cells (Frost et al., 2009). Further, we found that intracellular tau fibrils are released free into the media, where they propagate aggregation by direct interaction with native tau in recipient cells. An anti-tau antibody (HJ9.3) blocks this process by preventing tau aggregate uptake into recipient cells (Kfoury et al., 2012). In addition to similar experiments with recombinant tau (Guo and Lee, 2011), others have shown that paired helical filaments from AD brain induce cytoplasmic tau (-)-Catechin gallate aggregation (Santa-Maria et al., 2012). Injection of brain extract from human P301S tau transgenic mice into the brains of mice expressing wild-type human tau induces assembly of wild-type human tau into filaments and distributing of pathology (Clavaguera et al., 2009). Comparable effects occurred after injection of recombinant full-length or truncated tau fibrils, which caused quick induction of NFT-like inclusions that propagated from injected sites to connected brain regions in a time-dependent manner (Iba et al., 2013). Selective tau expression in the entorhinal cortex caused late pathology in the axonal terminal zones in cells in the dentate gyrus and hippocampus, consistent with trans-synaptic movement of aggregates (de Calignon et al., 2012; Liu et al., 2012). A growing body of work thus supports the idea that tau aggregates transfer between cells, and might be targeted with therapeutic antibodies. In mouse models that mimic aspects of AD and Parkinson’s disease, passive immunization using antibodies against A and alpha synuclein can reduce A and alpha-synuclein deposition in brain (Bard et al., 2000; DeMattos et al., 2001; Masliah et al., 2011), and improve behavioral deficits (Dodart et al., 2002; Kotilinek et al., 2002; Masliah et al., 2011). Active immunization in tauopathy mouse models using tau phospho peptides reduced tau pathology (Bi et al., 2011; Boimel et al., 2010) and in some studies improved behavior deficits (Asuni et al., 2007; Boutajangout et al., 2010; Troquier et al., 2012). In two passive vaccination studies, KIAA1819 there was reduced tau pathology and improved motor function when the antibody was given prior to the onset of pathology (Boutajangout et al., 2011; Chai et al., 2011). While several of the tau immunization studies appear to show some beneficial effects, the maximal expected efficacy of anti-tau antibodies administered after the onset of pathology, the optimal tau species to target, and the mechanism of the therapeutic effect have remained unknown. Our prior work in cell culture has suggested that aggregate flux in and out of cells might be central to progressive pathology (Kfoury et al., 2012). Thus, we predicted that antibodies that specifically block P301S brain-derived seeding activity might block propagation between cells and decrease overall tau pathology. We have used P301S human tau transgenic mice.