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Fig. 2. In the development of tau pathology, tau phosphorylation events are probably sequential. In the early stages of pathology (`pretangle'), the predominant phosphorylation events are probably those that decrease the ability of tau to bind microtubules rather than those that increase the ability of tau to self-associate; this might be caused by an imbalance in the activity of specific protein kinases or phosphatases (Ptases). For example, pretangle neurons in Alzheimer's disease brain are labelled with antibodies that recognize phospho-Thr231 and phospho-Ser262 (Augustinack et al., 2002) and phosphorylation of both of these sites significantly decreases interactions of tau with microtubules (Biernat et al., 1993; Cho and Johnson, 2003). Subsequently, tau can be cleaved by caspase and/or phosphorylated at additional sites such as Ser422 (Ferrari et al., 2003; Haase et al., 2004) and Ser396/404 (Abraha et al., 2000), which increases the propensity of tau to oligomerize and eventually form filamentous aggregates. The exact role that tau oligomers and filaments play in the cell dysfunction/death process has not yet been clearly defined.
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