Tau, Caspase Cleavage, and Apoptosis

The amyloid b peptide (Ab) that aggregates to form senile plaques in Alzheimer’s disease (AD) has long been thought to trigger the neurodegenerative process in this disease. However, the mechanism by which Ab exerts its toxic effect is not known. It has been established that the presence of tau is essential for Ab toxicity (Rapoport, et al., 2002). A growing body of evidence suggests that neurodegeneration may involve a process known as “apoptosis”, or programmed cell death. One aspect of this process is the activation of a class of proteases known as “caspases”. The tau protein contains three potential caspase cleavage sites, one of which is Asp⁴²¹. We have shown that tau truncated at this site polymerizes faster and to a greater extent than full-length tau (Role of the carboxy terminus). These considerations led us to propose and to test the hypothesis that exposure to Ab induces neuronal apoptosis, which results in caspase-mediated cleavage of tau, which in turn results in tau filament formation.

In biochemical studies, we were able to demonstrate that several caspases cleave tau, and that they cleave only at Asp⁴²¹. We then generated an antibody, TauC3, that is specific for tau truncated at Asp⁴²¹. This antibody does not recognize full-length tau or tau truncated at other sites. We used this antibody to show that exposure of cultured neurons to Ab induces caspase cleavage of tau. This is illustrated below in confocal images obtained from Ab-exposed rat cortical neurons in tissue culture. On the left, the green fluorescence indicates staining with an antibody against the microtubule protein, tubulin. The red fluorescence in the middle panel represents staining of caspase-cleaved tau by the TauC3 antibody. In the merged image on the right, colocalization of the two proteins creates a yellow color.

In addition to inducing caspase cleavage of tau, Ab also induced the cultured neurons to undergo nuclear condensation and fragmentation, another marker of apoptosis. Thus, in vitro, we have linked Ab exposure to neuronal apoptosis and implicated caspase-mediated tau cleavage in that process. To determine the relevance of these events to Alzheimer’s disease, we applied TauC3 to sections of brains of patients with this disease. In accordance with our hypothesis, and as shown below, this antibody revealed the typical AD triad of neurofibrillary tangles, neuritic plaques, and threads. Our findings support a mechanism for neurodegeneration in Alzheimer’s disease whereby Ab induces neuronal apoptosis and the resultant caspase-mediated cleavage of tau, leading to the toxic accumulation of tau filaments.

These studies are described in Gamblin, et al., 2003b.