Alzheimer disease hyperphosphorylated tau aggregates hydrophobically

Abstract

The chemical interaction that condenses the hyperphosphorylated protein tau in Alzheimer's disease (AD P-tau) into neurofibrillary tangles and cripples synaptic transmission remains unknown. Only β-sheet, positive ion salt bridges between phosphates, and hydrophobic association can create tangles of just AD P-tau. We have correlated transmission electron microscope (TEM) images of tau aggregation with different percentages of β-sheet in aqueous suspensions of tau while using buffers that block dispositive or tripositive ionic bridges between intermolecular phosphates. Circular dichroism (CD) studies were performed at different temperatures from 5-85°C using AD P-tau, AD P-tau dephosphorylated with hydrofluoric acid (HF AD P- tau) or alkaline phosphatase (AP AD P-tau), and recombinant human tau with 3- repeats and two amino terminal inserts (R-39) and using bovine tau (B tau) isolated without heat or acid treatment. Secondary structure was estimated from CD spectra at 5°C using the Lincomb algorithm. Each preparation except one demonstrated an inverse temperature transition, T(i), in the CD at 197 nm. No correlation was found between β-sheet content and aggregation, leaving only hydrophobic interaction as the remaining possibility. Thirteen of 21 possible phophorylation sites in AD P-tau lie adjacent to positive residues in tau's primary structure. Occupation of five to nine phosphate sites on AD P-tau appears sufficient to reduce or neutralize tau's basic character. AD P-tau's hydrophobic character is indicated by its low inverse temperature transition, T(i). The T(i) for AD P-tau was 24.5°C or 28°C, whereas for B tau with three phosphates it was 32°'C, for unphosphorylated tau R-39 it was 38°C, and for dephosphorylated HF AD P-tau it was 87,5°C. The hydrophobic protein elastin and its analogs coalesce and precipitate at their T(i) of 24-29°C, well below body temperature. We hypothesize that AD P-tau causes tangle accumulation by this mechanism.