Phospholipids alter tau conformation, phosphorylation, proteolysis, and association with microtubules: Implication for tau function under normal and degenerative conditions
✍ Scribed by Thomas B. Shea
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 131 KB
- Volume
- 50
- Category
- Article
- ISSN
- 0360-4012
No coin nor oath required. For personal study only.
✦ Synopsis
Discerning the in situ functions of the microtubuleassociated 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 F1 min induced antigenic alterations in multiple N-terminal, Cterminal 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 ␥-AT[ 32 P] 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 calpainmediated tau proteolysis. These data suggest that tau antigenicity in situ may be derived from phospholipiddependent 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.