Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?

After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on beta-amyloid peptide (A beta) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of A beta oligomers that form Ca(2+)permeable pores in the membranes of brain cells. By triggering an intracellular Ca(2+)overdose, A beta oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post-Ca(2+)entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing A beta oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti-oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico-based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This "histidine trick" can be viewed as the Achilles' heel of A beta in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of A beta oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti-oligomer targets will provide innovative opportunities to find an efficient cure. A "full efficient" solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.