Phosphorylation of tau, Aβ-formation, and apoptosis after in vivo inhibition of PP-1 and PP-2A

Chronic inhibition of protein phosphatases 1 and 2A in vivo was induced by infusion of okadaic acid into lateral ventricles of rat brain for up to 4 months. Cytoskeletal pathology, alterations of the amyloid precursor protein, and apoptotic cell death induced by this treatment followed a certain sequence and spatial distribution. Changes in the expression, phosphorylation, and subcellular distribution of neurofilament proteins and tau, as well as first signs of apoptotic cell death, occurred already after about 2 weeks. The distribution of apoptotic cells, however, was different from those revealing a high accumulation of hyperphosphorylated tau, indicating that those cytoskeletal pathology had no obvious sequelae fur the viability of these neurones. A continuation of treatment for longer than 2 weeks induced diffuse deposits of both hyperphosphorylated tau and alpha beta-amyloid-immunoreactive material in white matter areas that increased in size and number over time. Because tau-phosphorylation is a regulator of the dynamic stability of microtubules, the pathology observed in the present experimental paradigm in the white matter might be viewed as an indication of a disturbed axonal transport. It is hypothesized that perturbations of the axonal transport might also be critically involved in the formation of paired helical filaments and amyloid deposits in Alzheimer's disease. (C) 1998 Elsevier Science Inc.