Anti-tau oligomers passive vaccination for the treatment of Alzheimer disease

The aggregation and accumulation of the microtubule-associated protein (tau) is a pathological hallmark of Alzheimer disease (AD) and many neurodegenerative diseases. Despite the poor correlation between neurofibrillary tangles (NFTs) and disease progression, and evidence showing that neuronal loss in AD actually precedes NFTs formation, research until recently focused on them and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. Lately, the significance and toxicity of NFTs have been challenged and a new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of A beta toxicity in AD. Tau intermediate aggregate (tau oligomers; aggregates of an intermediate that is between monomers and NFTs in size) can cause neurodegeneration and memory impairment in the absence of A beta. This exciting body of evidence includes results from human brain samples, transgenic mouse and cell-based studies. Despite extensive efforts to develop a safe and efficacious vaccine for AD using A beta peptide as an immunogen in active vaccination approaches or anti A beta antibodies for passive vaccination, success has been modest. Nonetheless, these studies have produced a wealth of fundamental knowledge that has potential application to the development of a tau-based immunotherapy. Herein, I discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.