A? and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer's Disease?

In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic A? assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer's Disease (AD). However, the course of cognitive decline and AD development better correlates with tau accumulation rather than amyloid peptide deposition. Moreover, all clinical trials of amyloid-targeting drug candidates have been unsuccessful, implicitly suggesting that the amyloid hypothesis needs significant amendments. Accumulating evidence supports the existence of a series of potentially dangerous relationships between A? oligomeric species and tau protein in AD. However, the molecular determinants underlying pathogenic A?/tau cross interactions are not fully understood. Here, we discuss the common features of A? and tau molecules, with special emphasis on: (i) the critical role played by metal dyshomeostasis in promoting both A? and tau aggregation and oxidative stress, in AD; (ii) the effects of lipid membranes on A? and tau (co)-aggregation at the membrane interface; (iii) the potential of small peptide-based inhibitors of A? and tau misfolding as therapeutic tools in AD. Although the molecular mechanism underlying the direct A?/tau interaction remains largely unknown, the arguments discussed in this review may help reinforcing the current view of a synergistic A?/tau molecular crosstalk in AD and stimulate further research to mechanism elucidation and next-generation AD therapeutics.