This thesis investigates the intricate and complex mechanisms of tau protein propagation within the brain, with a particular focus on its implications in Alzheimer’s Disease and other tauopathies. Tau, a microtubule-associated protein, is essential for the maintenance of neuronal architecture and the facilitation of axonal transport. However, in the context of tauopathies, tau undergoes pathological modifications that result in the formation of insoluble aggregates.
A compelling aspect of tau pathology is its prion-like behavior, wherein misfolded tau acts as a pathogenic agent, inducing the misfolding and aggregation of normal tau proteins. This prion-like propagation is central to the dissemination of tau pathology throughout the brain. Our molecular studies have demonstrated that the seeding activity of tau isolated from postmortem brain tissue strongly correlates with the clinical progression of AD.
In addition, we have explored the interactions of tau with specific cellular receptors, notably LRP1 and SORL1. These receptors are critical in mediating the cellular uptake and internalization of tau, which not only facilitates its degradation but also promotes intracellular seeding mechanisms. This underscores the pivotal role of these receptors in the propagation of tau pathology.
Our research also addresses the heterogeneity of tau conformers and strains, which significantly contribute to the diverse clinical presentations observed in tauopathies. Tau proteins can misfold and aggregate into various conformations, each possessing distinct pathological properties. These conformers, or strains, propagate independently and induce unique patterns of tau misfolding. To accurately detect these variations, we have developed sophisticated biosensor cell lines with unparalleled sensitivity to tau seeding activity.
The diversity of tau strains is hypothesized to be a key determinant in the varying clinical manifestations and progression rates of tauopathies. By employing these advanced biosensors, we aim, in the future, to further our understanding of how specific tau strains drive pathological processes. On the longer term, this knowledge has the potential to inform the development of more precise diagnostic tools and targeted therapeutic strategies that address the unique conformational states of tau implicated in various neurodegenerative diseases.
