Hyperphosphorylated tau, the major component of the paired helical filaments of 
Alzheimer's disease, was found to accumulate in the brains of mice in which the 
calcineurin A alpha gene was disrupted [calcineurin A alpha knockout (CNA alpha 
-/-)]. The hyperphosphorylation involved several sites on tau, especially the 
Ser396 and/or Ser404 recognized by the PHF-1 monoclonal antibody. The increase 
in phosphorylated tau content occurred primarily in the mossy fibers of the CNA 
alpha -/- hippocampus, which contained the highest level of calcineurin in 
brains of wild-type mice. The CNA alpha -/- mossy fibers also contained less 
neurofilament protein than normal, although the overall level of neurofilament 
phosphorylation was unchanged. In the electron microscope, the mossy fibers of 
CNA alpha -/- mice exhibited abnormalities in their cytoskeleton and a lower 
neurofilament/microtubule ratio than those of wild-type animals. These findings 
indicate that hyperphosphorylated tau can accumulate in vivo as a result of 
reduced calcineurin activity and is accompanied by cytoskeletal changes that are 
likely to have functional consequences on the affected neurons. The CNA alpha 
-/- mice were found in a separate study to have deficits in learning and memory 
that may result in part from the cytoskeletal changes in the hippocampus.