Phospholipids alter tau conformation, phosphorylation, proteolysis, and association with microtubules: implication for tau function under normal and degenerative conditions.
Discerning the in situ functions of the microtubule-associated protein (MAP) tau is of interest both in terms of neuronal differentiation and homeostasis as well as in terms of neurodegenerative conditions such as Alzheimer's disease. In the present study, exposure to excess phosphatidyl serine (PS) for < 1 min induced antigenic alterations in multiple N-terminal, C-terminal and central epitopes of purified human brain tau. Notably, "AD-like" epitopes (PHF-1, ALZ-50, AT-8) were decreased by PS; other epitopes (e.g., 5E2, Tau-1) increased and others remained relatively unchanged. Inclusion of gamma-AT[32P] during incubations did not reveal any contaminating kinase activity. Direct addition of chloroform:methanol (CM; the initial PS solvent) demonstrated that these changes were not derived from CM-mediated tau denaturation. Phosphatidyl choline induced similar antigenic changes, while phosphatidyl inositol did not. PS inhibited MAP-kinase generation of phospho-dependent tau epitopes and incorporation of phosphates by tau. Inclusion of PS during coincubation of tau and tubulin reduced the extent of cosedimentation of tau with MTs. Finally, PS enhanced the ability of calpain-mediated tau proteolysis. These data suggest that tau antigenicity in situ may be derived from phospholipid-dependent alterations in tau conformation in addition to tau phosphorylation state. These data further suggest that disruption of the normal association of tau with phospholipids may foster accumulation of tau and, in doing so, render tau more susceptible to hyperphosphorylation.
Shea
T B
TB
Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts at Lowell, 01854, USA. SheaTH@woods.uml.edu
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D000918:Antibody Specificity; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002154:Calpain / Q000494:pharmacology; D002417:Cattle; D002474:Cell-Free System; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism*; D010718:Phosphatidylserines / Q000494:pharmacology; D010743:Phospholipids / Q000494:pharmacology*; D010766:Phosphorylation; D011487:Protein Conformation; D016875:tau Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
D010718:Phosphatidylserines; D010743:Phospholipids; D016875:tau Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002154:Calpain