Tangled tau: Active pathology or footprint of disease?

Alzheimer’s disease (AD) research is approaching crisis point. While disease prevalence relentlessly increases as the population ages, treatments are still limited in number and effect. There is little hope on the horizon as clinical trials for new AD drugs have a dishearteningly high failure rate– greater than any other field at 99.6% [1]. Most of the work on AD has focussed on beta-amyloid, with the importance of the microtubule-associated protein tau only being elucidated relatively recently. Tau-targeting treatments currently being tested, in clinical and preclinical settings, are geared toward preventing tau hyperphosphorylation and aggregation into neurofibrillary tangles (NFTs) [2]. However, there is a lack of consensus from animal models on whether these processes areworth targeting. Tau tangles may well correlate with disease severity and stage, but there is compelling evidence indicating that tangles represent a footprint of pathology, and soluble tau is the unseen culprit. Neurodegeneration and memory decline in mice expressing human P301L-tau was halted by the reduction of tau’s expression [3]. However, NFT accumulation continued unchanged, indicating that these aggregates are not sufficient to cause the observed phenotype. A further study demonstrated that memory impairment correlated with the presence of oligomeric soluble tau [4]. What is more, Drosophila engineered to express human tau exhibit similar cognitive defects and neurodegeneration but lack entirely the presence of NFTs [5]. Tau hyperphosphorylation by several kinases reduces its affinity for the microtubules and promotes aggregation, resulting in defective axonal transport and neuronal function which probably underpins certain aspects of the disease. Levels of hyperphosphorylated tau in human cerebrospinal fluid correlate well with disease severity and trajectory [6]. Yet, Drosophila displays an AD phenotype with minimal tau phosphorylation, although pathology was worsened by enhancing phosphorylation [7]. Furthermore, numerous phosphodeficient tau mutants retain their toxicity [8]. Hyperphosphorylation likely results in both gain-of-toxicity