From the Cover: Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

摘要

To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer’s disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-β protein (Aβ). This complex enhances tau phosphorylation by GSK3β, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. Aβ binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple Aβ peptides in the mid to C-terminal regions of Aβ. This binding is also significantly decreased by GSK3β phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of Aβ for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected Aβ bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and Aβ form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble Aβ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and Aβ nucleation. Blocking the sites where Aβ initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.