Cytoskeletal Changes in the Brains of Mice Lacking Calcineurin Aα

Abstract: Hyperphosphorylated τ, 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 Aα gene was disrupted calcineurin Aα knockout (CNAα^?/?)]. The hyperphosphorylation involved several sites on τ, especially the Ser³⁹⁶ and/or Ser⁴⁰⁴ recognized by the PHF-1 monoclonal antibody. The increase in phosphorylated τ content occurred primarily in the mossy fibers of the CNAα^?/? hippocampus, which contained the highest level of calcineurin in brains of wild-type mice. The CNAα^?/? 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 CNAα^?/? mice exhibited abnormalities in their cytoskeleton and a lower neurofilament/microtubule ratio than those of wild-type animals. These findings indicate that hyperphosphorylated τ 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 CNAα^?/? 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.