FREE FATTY-ACIDS STIMULATE THE POLYMERIZATION OF TAU-PEPTIDES AND AMYLOID-BETA-PEPTIDES - IN-VITRO EVIDENCE FOR A COMMON EFFECTOR OF PATHOGENESIS IN ALZHEIMERS-DISEASE

Alzheimer's disease is a degenerative disorder of the central nervous system, characterized by the concomitant deposition of extracellular f ilaments composed of beta-amyloid peptides and intracellular filaments composed of the microtubule-associated protein tall. We have discover ed that free fatty acids (FFAs) stimulate the assembly of both amyloid and tau filaments in vitro. The minimal concentration of arachinonic acid observed to stimulate tall assembly ranged from 10 to 20 mu mol/L , depending on the source of the purified tau. Tall preparations that no not exhibit spontaneous assembly were among those induced to polyme rize by arachidonic acid. All long-chain FFAs tested enhanced assembly to some extent, although greater stimulation was usually associated w ith unsaturated forms. Utilizing fluorescence spectroscopy, unsaturate d FFAs were also demonstrated to induce beta-amyloid assembly. The min imal concentration of oleic or linoleic acid observed to stimulate the assembly of amyloid was 40 mu mol/L. The filamentous nature of these thioflavin-binding amyloid polymers was verified by electron microscop y. These data define a new set of tools for examining the polymerizati on of amyloid and tau proteins and suggest that cortical elevations of FFAs may constitute a unifying stimulatory event driving the formulat ion of two of the obvious pathogenetic lesions in Alzheimer's disease.