IECB SEMINAR JULY 4TH @ 11am

 Dr. Noé QUITTOT from  Harvard Medical School (HMS) Boston USA

 Will present a seminar entitled: "Uncovering Rare and Potent Non-Fibrillar Tau Aggregates in Alzheimer’s Brain"

In Alzheimer’s disease (AD), the abnormal accumulation of hyperphosphorylated Tau is a well-known pathological feature. Among the various Tau assemblies present in the human AD brain, a subset of nonfibrillar high molecular weight (HMW) species—likely oligomers—has emerged as bioactive, i.e., capable of inducing templated misfolding of native Tau. However, the defining characteristics that render these diffusible species seed-competent have remained elusive. In this study, we used anion exchange chromatography to fractionate HMW Tau and uncovered several subspecies distinguished by their charge. Interestingly, only the highly charged variants showed seeding activity, while the less charged forms were inert—yet both were present across all AD cases examined. Despite similar size and morphology, as confirmed by super-resolution microscopy, atomic force microscopy, and immunogold electron microscopy, only the charged Tau assemblies could seed aggregation. Recent single molecule array (SIMOA)-based analyses confirmed that surface charge correlates with bioactivity. Remarkably, we found that just a few hundred molecules of soluble Tau derived from the AD brain are sufficient to induce aggregation in biosensor cells and follow a single-hit kinetic model, consistent with prion-like behavior. Altogether, our findings provide new insight into the molecular features that define bioactive Tau species in AD and underline the extreme rarity of these potent seeds—even in advanced disease—raising important questions for future therapeutic strategiesIn Alzheimer’s disease (AD), the abnormal accumulation of hyperphosphorylated Tau is a well-known pathological feature. Among the various Tau assemblies present in the human AD brain, a subset of nonfibrillar high molecular weight (HMW) species—likely oligomers—has emerged as bioactive, i.e., capable of inducing templated misfolding of native Tau. However, the defining characteristics that render these diffusible species seed-competent have remained elusive. In this study, we used anion exchange chromatography to fractionate HMW Tau and uncovered several subspecies distinguished by their charge. Interestingly, only the highly charged variants showed seeding activity, while the less charged forms were inert—yet both were present across all AD cases examined. Despite similar size and morphology, as confirmed by super-resolution microscopy, atomic force microscopy, and immunogold electron microscopy, only the charged Tau assemblies could seed aggregation. Recent single molecule array (SIMOA)-based analyses confirmed that surface charge correlates with bioactivity. Remarkably, we found that just a few hundred molecules of soluble Tau derived from the AD brain are sufficient to induce aggregation in biosensor cells and follow a single-hit kinetic model, consistent with prion-like behavior. Altogether, our findings provide new insight into the molecular features that define bioactive Tau species in AD and underline the extreme rarity of these potent seeds—even in advanced disease—raising important questions for future therapeutic strategies.