Abstract
Aggregated and highly phosphorylated tau protein is a pathological
hallmark of Alzheimer's disease (AD) and other tauopathies. We identified
motifs of alternating polar and apolar amino acids within the microtubule-binding
repeats of tau which were interrupted by small breaking stretches.
Minimal mutation of these breaking sequences yielded a unique instantly
aggregating tau mutant containing longer stretches of polar/apolar
amino acids without losing its microtubule-binding capacity. These
modifications produced rapid aggregation and cytotoxicity with accompanying
occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270,
AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and
Alz50) in cells. Similar to pathological tau in the pretangle state,
toxicity appeared to occur early without the requirement for extensive
fibril formation. Thus, our mutant protein provides a novel platform
for the investigation of the molecular mechanisms for toxicity and
cellular behavior of pathologically aggregated tau proteins and the
identification of its interaction partners.
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