Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy.

Neurofibrillary tangles (NFTs) have been implicated in mediating neuronal death and disease progression in human tauopathies; however, mounting in vivo data suggest that NFTs may not be the primary initiators of neurotoxicity. Caspase activity has been implicated in processes associated with the development of tauopathy, but the position that caspase activation holds in neurodegenerative cascades remains uncertain. Using multiphoton real-time imaging microscopy, de Calignon et al recently demonstrated that caspase activation precedes and leads to tangle formation within 24 hours in the rTg4510 mouse model of tauopathy. Here, we used immunoelectron microscopy to determine whether caspase-cleaved tau was present in NFTs of rTg4510 mice. Using a caspase-cleaved tau-specific antibody (TauC3), we found very little immunogold labeling in NFTs in the brains of rTg4510 mice. By immunohistochemistry, the number of TauC3-positive neurons was far less than the numbers of neurons stained with the MC1 antibody, which recognizes abnormal conformations of tau. Biochemically, caspase-cleaved tau was barely detectable in fractions of rTg4510 mouse brain extracts. Our data suggest that caspase activation might be one of multiple routes through which NFT formation occurs, rather than an obligatory initiation step in pathologic tau production in rTg4510 mice.