Amyloid-based therapies did fail again! It is the right time to change our vision on building block of Alzheimer's disease

Alois Alzheimer, the Bavarian neuropathologist, first introduced the Alzheimer's disease (AD) in 1906 following detection of amyloid plaques, neurofibrillary tangles, and arteriosclerotic changes in the brain of his patient. AD is known as the most frequent global form of dementia, these days, representing 50-80% of all cases1 with huge patient maintenance costs (i.e. 172 billion US dollars in 2010 at the United States1 predicting to reach 1 trillion dollars by 2050).2 The most well recognized hallmarks of AD neuropathology known now are the extracellular amyloid plaque burden, intracellular neurofibrillary tangles, and microtubule destabilizations.3 Misfolding each of these proteinaceous entities have their specific mechanisms to contribute to neuronal cell death and have been the subject of plethora of researches in the last decade.3 The amyloid hypothesis is recognized as the most plausible culprit for inducing AD and the therapeutic approaches were developed based on detachments of fibril monomers.3 However, failure of these approaches (for instance, the two bapineuzumab and solanezumab drugs, in phase III trials, were failed in 2012) raised the concerns whether the treatment approaches were designed in the right way (there is crucial questioning on the validity of Aβ hypothesis). Recently, the regulations of multivalent cations (i.e. Zn2+, Cu2+, Mn≥2+, Fe≥2+, and Co≥2+) in biological fluids have been received great attentions for AD community. The reason of this considerable attention is the fact that the unbalanced multivalent cations can act as linker among negatively charged Aβ monomers, and initiate the oligomerization process.3 Deep postmortem investigation, on the brain tissues of AD individuals, showed remarkable presence of multivalent cations in amyloid plaques.3 From the physiological points of view, similar to other tissues, the multivalent cations play crucial role in brain and are heterogeneously distributed with relatively high concentrations throughout the brain, due to the specific biological demands. As multivalent cations are inevitable parts of many proteins and enzymes possessing remarkable portions of human proteome, they may carry neuroprotective and neurotrophic properties in brain during ageing and restoration processes. However, studies have shown that these multivalent cations can strongly induce different aggregation pathways by utilizing the specific structural elements of human Aβ and potentially contribute to oxidative stress address the question whether their dyshomeostasis is the key cause for initiation of early molecular changes toward AD, repositioning the amyloid hypothesis in AD pathology. Iranian Journal of Neurology