%0 Journal Article
%T Caspase-Mediated Truncation of Tau Potentiates Aggregation
%A Sangmook Lee
%A Thomas B. Shea
%J International Journal of Alzheimer's Disease
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/731063
%X Caspase-mediated truncation of tau is associated with aggregation. We examined the impact of manipulation of caspase activity on intracellular aggregation of a mutant form of tau (3PO) that forms spontaneous aggregates. Treatment with the caspase inhibitor Z-VAD-fmk reduced both N and C-terminal tau truncation but did not significantly reduce aggregation. Treatment with staurosporine, which activated caspases, increased C-terminal but not N-terminal truncation and enhanced aggregation. These findings suggest that caspase activation is one potential route, rather than an obligatory initiation step, in aggregation, and that N- and C-terminal truncation contribute differentially to aggregation. One pathological hallmark of tauopathies is aggregation of the microtubule-associated protein tau. A growing body of evidence highlights the importance of truncation in initiation and potentiation of tau aggregation [1¨C8]. Tau truncated at amino acid D421 has been detected in Alzheimer¡¯s disease (AD) [3, 4, 9, 10] and other tauopathies [11]. C-terminal truncation of tau introduces a conformational change, along with phosphorylation, contributes to aggregation [12¨C14]. Caspases are serine-aspartyl proteases typically considered to be activated during apoptosis, but can also be activated without apoptosis [15]. In this regard, while caspase activation precedes and promotes tangle formation [1], tangle-bearing neurons can survive for extended periods [16, 17]. Cleavage of tau at D421 has been suggested to be mediated by caspase-3 [3, 4]. By contrast, analyses of transgenic mice suggest that caspase-6, rather than caspase-3, may truncate tau at D421 [8]. Additional analyses in mice suggest that caspase activation may not be obligatory for tangle initiation, but rather may represent one of multiple mechanisms contributing to tau aggregation [18]. Truncation of tau at D13, which can also be mediated by caspase-6 [19], has been detected in AD brains [20]. Whether caspase-6 mediates this cleavage in situ is unclear [20, 21]. Any role for N-terminal cleavage in aggregation remains to be elucidated. Herein, we present evidence that tau truncation at D421 is not necessarily mediated by caspase-3 and that neither N- nor C- terminal truncation is essential for aggregation. NB2a/d1 cells were cultured and transfected as described [22] with a plasmid expressing GFP (Green Fluorescent Protein) tagged 3£¿PO tau, a mutated form of human tau that spontaneously aggregates but retains its microtubule binding capacity (gift of Dr. F. S. Wouters, Max-Planck-Institute, Germany) [23]. Medium
%U http://www.hindawi.com/journals/ijad/2012/731063/