Caspase‐6‐mediated tau cleavage and pathology in Alzheimer’s disease and other tauopathies

Abstract

AbstractBackgroundCaspases are being explored as targets for pharmacological treatment of tauopathies due to their role in tau cleavage, which leads to tau aggregation and neuronal loss. Tau truncated at Asp421, a residue cleaved by effector caspases, is found in four common tauopathies: Alzheimer’s disease (AD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP) (Newman et al., 2005). We previously demonstrated that active caspase‐6 colocalizes with neurons containing phosphorylated tau during early AD stages and that the number of neurons positive for both active caspase‐6 and p‐tau increases throughout AD's progression. However, how caspase‐6 activity differs between tauopathies involving different tau isoforms is unknown. This study compares caspase‐6 activation and caspase‐6 cleavage of tau between AD, argyrophilic grain disease (AGD), CBD, PiD, and PSP using novel neoepitope antibodies against caspase‐6‐cleaved tau.MethodUsing multiplex immunofluorescence on tissue microarrays, we measured levels of neuronal active caspase‐6, tau cleaved at C‐terminal residue D402 (D402), tau cleaved at N‐terminal residue D13 (D13), and tau phosphorylated at Ser202 (p‐tau; CP13) in the middle frontal gyrus (MFG) of well‐characterized AD, AGD, CBD, PiD, and PSP cases and controls. We used semi‐automated methods to calculate the percentage of neurons positive for each marker.ResultWe found similar percentages of neuronal p‐tau in every tauopathy except AGD, as expected. Only AD and PiD showed substantial percentages of neuronal caspase‐6‐cleaved tau (Figure 1, Table 1). The mean percentages of neuronal D402 and D13 were up to 121.88‐fold higher in AD and up to 16.75‐fold higher in PiD compared to the other tauopathies (Figure 1, Table 1). In PiD, on average, 79.82‐87.61% of neurons positive for D402 or D13 were also positive for p‐tau. Interestingly, in AD, only an average of 50.70‐58.98% of neurons positive for D402 or D13 showed p‐tau positivity (Figure 2).Conclusion1) Caspase‐6‐cleavage of tau appears to be a more defining feature of tauopathies involving 3‐repeat isoforms of tau than 4‐repeat tauopathies. 2) Caspase‐6‐cleaved tau inclusions do not necessarily colocalize with p‐tau inclusions. 3) Future research on the therapeutic potential of caspase modulators should focus on AD and PiD.