Functional Selection of Tau Oligomerization‐Inhibiting Aptamers

Abstract: Pathological hyperphosphorylation and aggregation of microtubule‐associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next‐generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd = 6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)‐induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β‐mediated Tau hyperphosphorylation in cell‐free systems and okadaic acid‐mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro‐orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first‐in‐class neurotherapeutic to mitigate tauopathy‐associated neurodegenerative disorders.