Phosphorylation sensitizes microtubule-associated protein tau to Al(3+)-induced aggregation.
In Alzheimer's disease the microtubule-associated protein tau becomes hyperphosphorylated and aggregates into paired helical filaments (PHFs). Although the biochemical basis of the aggregation of tau into PHFs is not very clear, Al3+ has been suggested to play some role. Previous studies have shown that Al3+ alters the phosphorylation state and causes aggregation of tau in experimental animals and cultured neurons. In this study Al3+ inhibited phosphorylation of tau by neuronal cdc2-like kinase and dephosphorylation of phosphorylated tau by phosphatase 2B. These inhibitions are very likely due to Al(3+)-induced aggregations of various proteins present in phosphorylation/dephosphorylation assay mixtures since Al3+ caused aggregations of all proteins examined. Furthermore, compared to other proteins, tau displayed only an average sensitivity towards Al(3+)-induced aggregation. However upon phosphorylation, tau's sensitivity towards Al3+ increased 3.5 fold. In the presence of the metal chelator EDTA, Al(3+)-induced aggregates of tau became soluble, whereas Al(3+)-induced phosphorylated tau aggregates were insoluble in the buffer containing EDTA and remained insensitive to proteolysis. Our data suggest that phosphorylation sensitizes tau to Al3+ and phosphorylated tau transforms irreversibly into a phosphatase and protease resistant aggregate in presence of this metal ion.
Li
W
W
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Ma
K K
KK
Sun
W
W
Paudel
H K
HK
D000534:Alum Compounds / Q000494:pharmacology; D000535:Aluminum / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000494:pharmacology; D066298:In Vitro Techniques; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000187:drug effects; D011817:Rabbits; D016875:tau Proteins / Q000737:chemistry* / Q000187:drug effects
D000534:Alum Compounds; D011506:Proteins; D016875:tau Proteins; C041524:aluminum sulfate; D000535:Aluminum; D016203:CDC2 Protein Kinase