Cytoskeletal changes in the brains of mice lacking calcineurin A alpha.
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.
Kayyali
U S
US
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhang
W
W
Yee
A G
AG
Seidman
J G
JG
Potter
H
H
D000818:Animals; D000918:Antibody Specificity; D001923:Brain Chemistry / Q000502:physiology*; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D016296:Mutagenesis / Q000502:physiology; D016900:Neurofilament Proteins / Q000032:analysis / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D016875:tau Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism
D002148:Calmodulin-Binding Proteins; D016900:Neurofilament Proteins; D016875:tau Proteins; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases