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Considerations for future tau-targeted therapeutics: can they deliver?

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and a leading cause of death. The progressive accumulation and spread of β-amyloid and tau in AD brain are linkedwith synaptic loss and neurodegeneration. Recent evidence indicates that while alterations in amyloid precursor protein processing and β-amyloid accumulation likely trigger AD, abnormal tau acts as the executioner. Tau is normally a highly soluble cytoplasmic protein that dynamically interacts with microtubules to stabilize the cytoskeleton and regulate axonal transport. When modified, including by hyperphosphorylation, cleavage and aggregation, tau accumulates as neurofibrillary pathology in AD and related tauopathies such as progressive supranuclear palsy (PSP) and some forms of frontotemporal dementia (FTD) [1]. Pathological tau species show altered interactions and localization, loss of physiological function, prion-like spread characteristics that promote the progressive appearance of tau pathology through diseased brain, and gain of toxic functions. For example, the mislocalization of pathological tau from the cytoplasm to synapses causes loss of presynaptic function, promotes post-synaptic excitotoxicity, and is closely associated with dementia in AD [1,2]. Here, we discuss the current state of tau-targeting therapies.