Misfolded tau proteins undergo pathological alterations, aggregating into fibrils that subsequently form neurofibrillary tangles, the hallmark of neurodegeneration in tauopathies, including Alzheimer's disease (AD). The accumulation of misfolded tau in neurons disrupts cellular physiology, leading to neuronal death and the propagation of tau misfolding throughout the brain. The presence of pathological tau protein in the brain also affects microglia, which play a crucial role in the uptake and clearance of tau aggregates, on the other hand, microglia activity causes chronic neuroinflammation which further damages neurons. Despite advancements in understanding tau pathology, the relationships between initial tau misfolding, fibril formation, the propagation of pathology across connected neurons, and subsequent cytotoxicity on the level of individual neurons and microglia remain unclear.
We employ in situ cryo-ET to investigate the ultrastructural aspects of the uptake of AD tau fibrils by neuroblastoma and microglia. Our focus is on morphological information about tau neurofibrils and their interactions within neurons, with an emphasis on the cytoskeleton, mitochondria, and degradation machinery. Regarding microglia, we concentrate on AD tau fibril phagocytosis and degradation.
In this poster, we present our in situ visualization workflow and showcase preliminary cryo-ET data of AD-tau fibril intake by neuroblastoma and microglia.
This work has received funding from the Czech Science Foundation (22-15175I). We acknowledge CF CryoEM of CIISB, Instruct-CZ Centre, supported by MEYS CR (LM2023042) ) and European Regional Development Fund-Project „UP CIISB“ (No. CZ.02.1.01/0.0/0.0/18_046/0015974).