Tau aggregates in neurodegenerative diseases: cause or consequence of autophagic dysfunction?

Tauopathies are neurodegenerative diseases, with Alzheimer’s disease (AD) being the most common one, all characterized by abnormal accumulation of insoluble Tau aggregates. These latter propagate in patients’ brain in a stereotypical manner following a prion-like mechanism and cause movement disorders, dementia, and cognitive decline. Several tauopathies share defects in the autophagy-lysosomal system, the primary route for clearance of protein aggregates. Upon receptors recognition, aggregates are engulfed by autophagosomes, that eventually deliver them to lysosomes for degradation. However, it remains to be elucidated whether accumulation of Tau aggregates is the cause or the consequence of autophagic impairment in tauopathies, and whether Tau aggregates can be degraded by autophagy in physiological condition. During my internship, a neuronal cell model of neuroblastoma SH-SY5Y cells expressing fluorescently labeled FL-Tau1N4R (P301S) aggregates was used to investigate whether FL-Tau aggregates could affect autophagic flux and activity, to monitor their half-life and to understand if they are degraded by autophagy. My findings suggested that FL-Tau aggregates seemed not to impair autophagic flux nor activity and that they were likely to be recognized by autophagic receptors, but their clearance was not efficient. Additionally, my results highlighted the importance to develop a reliable model to clarify the controversial relationship between Tau aggregates and autophagic defects in tauopathies.