398 COMMENTARY ON ANDERTON ET AL.

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COMMENTARY

ABNORMAL HYPERPHOSPHORYLATION OF TAU: PARTICIPATION OF/~-AMYLOID/PEPTIDE OUT AND PROLINE-DIRECTED

PROTEIN KINASES (PDPKs) AND NON-PDPKs IN

K H A L I D IQBAL A N D INGE G R U N D K E - I Q B A L

New York State Institute for Basic Research in Developmental Disabilities, Staten Island, N Y 10314

DATA on the modulation of tau hyperphosphorylation in tis- sue culture by Anderton et al. is very exciting. The dephosphor- ylation of tau observed in g lu tamate -and colchicine-treated primary neurons by Anderton et al. is opposite to the increase in phosphorylation that is observed in Alzheimer's disease. Fur- thermore, these authors did not find any synergistic effect of /3-amyloid and glutamate on tau phosphorylation and unlike previous claims in the literature, the/3-amyloid alone was found to have no effect on tau phosphorylation in the neuronal cultures.

Consistent with these studies, we have been unable to induce any abnormal phosphorylation of tau in rat brain injected with either 13-peptide or/3-amyloid isolated from AD brain (4). Fur- thermore, unlike Shin et al. (5), in our studies injection of AD abnormally phosphorylated tau did not produce any accumu- lation of tau-positive fibrils at the injection sites.

Ever since the discoveries of tau as the major protein sub- unit of Alzheimer PHF-(1) and the abnormal phosphorylation of tau in AD brain, especially PHF (2,3), many efforts have been made on the identification of the protein kinases involved in the tau hyperphosphorylation. Of these studies, most attention has been drawn by those on hyperphosphorylation of tau by

proline-directed protein kinases (PDPKs), MAP kinase, GSK-3, and members of cyclin-dependent kinases. Findings that during development tau is hyperphosphorylated at some of the same sites as AD abnormally phosphorylated tau has led several inves- tigators to suggest that AD abnormal phosphorylation of tau is a recapitulation of the events of neurodevelopment. Thanks

to the recent work of Morishima-Kawashima et al. (this issue) it is now clear (a) that PHF-tau is hyperphosphorylated at 21 sites; (b) that fetal tau is phosphorylated at less than one-half of those sites; (c) that only approximately one-half of the phos- phorylation sites in PHF-tau are cannonical sites for PDPKs and remaining half of the sites are non-PDPK sites. In light of these findings, it is clear that the AD abnormally phosphorylated tau is a product of phosphorylation by both PDPKs and non-PDPKs. Thus, transfection studies of Anderton et al. are interesting in that they suggest that in the transfected ceils GSK-3 and not MAP kinase appear to be involved in hyperphosphorylation of tau. However, these findings should not be taken as that only GSK-3 can produce AD abnormally phosphorylated tau. Phos- phorylation of tau by one kinase(s) probably modulates the phosphorylation of tau by another kinase(s) at different sites. This type of site-site interaction produced by PDPKs and non- PDPKs is probably involved in the abnormal hyperphosphor- ylation of tau in AD (6). This possibility is further supported by the fact that to date all abnormal hyperphosphorylation of tau by any of the PDPKs was achieved in 16-24 h of in vitro phosphorylation. Under these conditions kinetically unfavorable sites are phosphorylated.

In conclusion,/3-amyloid (peptide) neurotoxicity does not produce hyperphosphorylation of tan. Alzheimer's disease ab- normal hyperphosphorylation of tau probably involves site- site interaction and participation of both proline-directed and nonproline-directed protein kinases in these modulations.

REFERENCES

1. Grundke-Iqbal, I.; lqbal, K.; Quinlan, M.; Tung, Y.-C.; Zaidi, M. S.; Wisniewski, H. M. Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J. Biol. Chem. 261:6084-6089; 1986.

2. Grundke-Iqbal, I.; Iqbal, K.; Tung, Y.-C.; Quinlan, M.; Wisniewski, H. M.; Binder, L. I. Abnormal phosphorylation of the microtubule- associated protein tau in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci USA 83:4913-1917; 1986.

3. Iqbal, K.; Grundke-Iqbal, I.; Zaidi, T.; Merz, P. A.; Wen, G. Y.; Shaikh, S. S.; Wisniewski, H. M.; Alafuzoff, I.; Winblad, B. Defec- tive brain microtubule assembly in Alzheimer's disease. Lancet 2:421- 426; 1986.

4. Kudo, T.; Tanaka, T.; Takeda, M.; Nishimura, T.; Grundke-lqbal, I.; Iqbal, K. Neuropathological changes in rat brain injected with Alz- heimer tau, paired helical filaments, and amyloid cores. Neurobiol. Aging 15 (Suppl. 1):Sll3; 1994.

5. Shin, R. W.; Bramblett, G. T.; Lee, V. M.-Y.; Trojanowski, J. Q. Alzheimer disease A68 proteins injected into rat brain induce co- deposits of/3-amyloid, ubiquitin, and ~ 1-antichymotrypsin. Proc. Natl. Acad. Sci. USA 90:6825-6828; 1993.

6. Singh, T. J.; Zaidi, T.; Grundke-Iqbal, I.; lqbal, K. (1994) Modu- lation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by nonproline dependent protein kinases. FEBS Lett. 358:4-8; 1995.