Alzheimer disease hyperphosphorylated tau aggregates hydrophobically.
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 beta-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 beta-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 degrees 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 degrees C using the Lincomb algorithm. Each preparation except one demonstrated an inverse temperature transition, Ti, in the CD at 197 nm. No correlation was found between beta-sheet content and aggregation, leaving only hydrophobic interaction as the remaining possibility. Thirteen of 21 possible phosphorylation 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, Ti. The Ti for AD P-tau was 24.5 degrees C or 28 degrees C, whereas for B tau with three phosphates it was 32 degrees C, for unphosphorylated tau R-39 it was 38 degrees C, and for dephosphorylated HF AD P-tau it was 37.5 degrees C. The hydrophobic protein elastin and its analogs coalesce and precipitate at their Ti of 24-29 degrees C, well below body temperature. We hypothesize that AD P-tau causes tangle accumulation by this mechanism.
Ruben
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GC
Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755, USA. George.C.Ruben@Dartmouth.Edu
Ciardelli
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TL
Grundke-Iqbal
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Iqbal
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D000469:Alkaline Phosphatase / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D005260:Female; D005333:Fetus / Q000378:metabolism; D006801:Humans; D006858:Hydrofluoric Acid; D008854:Microscopy, Electron; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D016622:Silver Staining; D013696:Temperature; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
D011994:Recombinant Proteins; D016875:tau Proteins; D000469:Alkaline Phosphatase; D006858:Hydrofluoric Acid