The tangles of
Alzheimer's disease (AD) are comprised of the
tau protein displaying numerous alterations, including phosphorylation at
serine 422 (S422) and truncation at
aspartic acid 421 (D421). Truncation at the latter site appears to result from activation of
caspases, a class of
proteases that cleave specifically at
aspartic acid residues. It has been proposed that phosphorylation at or near
caspase cleavage sites could regulate the ability of the
protease to cleave at those sites. Here, we use tau pseudophosphorylated at S422 (S422E) to examine the effects of tau phosphorylation on its cleavage by
caspase 3. We find that S422E tau is more resistant to proteolysis by
caspase 3 than non-pseudophosphorylated tau. Additionally, we use
antibodies directed against the phosphorylation site and against the truncation
epitope to assess the presence of these
epitopes in neurofibrillary tangles in the aged human brain. We show that phosphorylation precedes truncation during tangle maturation. Moreover, the distribution of the two
epitopes suggests that a significant length of time (perhaps as much as two decades) elapses between S422 phosphorylation and cleavage at D421. We further conclude that tau phosphorylation at S422 may be a protective mechanism that inhibits cleavage in vivo.