Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

Abstract

Hyperphosphorylated tau, which is the major protein of the neurofibrillary tangles in Alzheimer's disease brain, is most probably the result of an imbalance of tau kinase and phosphatase activities in the affected neurons. By using metabolically competent rat brain slices as a model, we found that selective inhibition of protein phosphatase 2A by okadaic acid induced an Alzheimerlike hyperphosphorylation and accumulation of tau. The hyperphosphorylated tau had a reduced ability to bind to microtubules and to promote microtubule assembly in vitro. Immunocytochemical staining revealed hyperphosphorylated tau accumulation in pyramidal neurons in cornu ammonis and in neocortical neurons. The topography of these changes recalls the distribution of neurofibrillary tangles in Alzheimer's disease brain. Selective inhibition of protein phosphatase 2B with cyclosporin A did not have any significant effect on tau phosphorylation, accumulation, or function. These studies suggest that protein phosphatase 2A participates in regulation of tau phosphorylation, processing, and function in vivo. A down-regulation of protein phosphatase 2A activity can lead to Alzheimer-like abnormal hyperphosphorylation of tau.

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

“…Metabolically active brain slices (400 μm × 400 μm) were prepared from 6.5‐month‐old male Wistar rats and incubated in oxygenated artificial cerebrospinal fluid (CSF), as described (Gong et al ., 2000). 0.2 m m O ‐(2‐acetamido‐2‐deoxy‐ d ‐glucopyranosylidene) amino‐ N ‐phenylcarbonate (PUGNAc) was added to the artificial CSF during incubation.…”

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

“…Previous studies revealed that down-regulation of protein phosphatases or up-regulation of protein kinases are the main causes for tau hyperphosphorylation. Protein phosphatase 2A (PP2A), a major tau phosphatase in the brain, is recognized as a promising candidate that may participate in the regulation of tau phosphorylation in AD [1] .…”

DSCR1(Adapt78)‐‐A Janus Gene Providing Stress Protection but Causing Alzheimer's Disease?

“…Comparison of AD and control samples has demonstrated that cyclophilin A and FKBP12 are not altered in AD (8,11). Calcipressin 1, which is expressed in neuronal cells, is however upregulated in AD brains (12).…”