Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease.
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 Alzheimer-like 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.
Gong
C X
CX
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314-6399, USA.
Lidsky
T
T
Wegiel
J
J
Zuck
L
L
Grundke-Iqbal
I
I
Iqbal
K
K
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008870:Microtubules / Q000201:enzymology / Q000378:metabolism; D019579:Neocortex / Q000201:enzymology / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D051381:Rats; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016875:tau Proteins; D019319:Okadaic Acid; D007770:L-Lactate Dehydrogenase; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2