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Functional Selection of Tau Oligomerization-Inhibiting Aptamers
Bang Wang1,2, Xiaoshu Pan1, I-Ting Teng1
1Department of Chemistry and Department of Physiology and Functional Genomics, Center for Research at Bio/Nano Interface, Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 32611, USA.
Researchers developed novel DNA aptamers targeting Tau protein to combat Alzheimer's Disease (AD). One aptamer, BW1c, inhibits Tau aggregation and hyperphosphorylation, crossing the blood-brain barrier for potential neurotherapeutics.
Area of Science:
- Biotechnology
- Neuroscience
- Molecular Biology
Background:
- Pathological Tau protein hyperphosphorylation and aggregation are hallmarks of Alzheimer's Disease (AD) and tauopathies.
- Current treatments for AD are limited, highlighting the need for novel therapeutic strategies.
- Aptamers show promise as next-generation therapeutics for neurological disorders.
Purpose of the Study:
- To develop a novel selection strategy for identifying DNA aptamers that bind to monomeric Tau protein and inhibit its pathological aggregation.
- To characterize the binding affinity and inhibitory effects of selected aptamers on Tau protein.
- To evaluate the potential of these aptamers as neurotherapeutics for tauopathies.
Main Methods:
- A new aptamer selection strategy was employed to enrich DNA aptamers binding to monomeric Tau protein under aggregation-promoting conditions.
- Selected aptamer candidates were assessed for binding affinity to Tau protein using Kd measurements.
- The inhibitory effects of aptamers on Tau protein oligomerization, aggregation, and hyperphosphorylation (induced by arachidonic acid, GSK3β, and okadaic acid) were evaluated in cell-free and cellular systems.
- The ability of an aptamer to cross the blood-brain barrier was assessed via retro-orbital injection.
Main Results:
- A set of aptamer candidates targeting Tau protein was identified using the novel selection strategy.
- The aptamer BW1c exhibited high binding affinity (Kd=6.6 nM) to Tau protein.
- BW1c effectively inhibited arachidonic acid-induced Tau protein oligomerization and aggregation.
- BW1c demonstrated inhibition of GSK3β-mediated and okadaic acid-mediated Tau hyperphosphorylation in vitro and in cells.
- BW1c was shown to cross the blood-brain barrier and reach neuronal cell bodies.
Conclusions:
- The developed aptamer selection strategy successfully identified DNA aptamers with high affinity for Tau protein.
- The aptamer BW1c shows significant potential by inhibiting key pathological mechanisms of Tau in Alzheimer's Disease.
- BW1c's ability to cross the blood-brain barrier suggests its promise as a first-in-class neurotherapeutic for tauopathy-associated neurodegenerative disorders.
