Lecture: Neuronal cell models to investigate diversity of pathological tau conformers

When: 18 June 2024 from 13:00
Where: room S12
Who: Mgr. Lenka Hromádková, PhD. (Case Western Reserve University, Cleveland, Ohio)

Abstract: Although accumulation of misfolded tau species has been shown to be a predictor of cognitive decline in patients with Alzheimer’s disease (AD) and other tauopathies as well, a remarkable heterogeneity of clinical manifestations, neuropathology profiles, and time courses of disease progression remain unexplained by current genetic data. We considered the diversity of misfolded tau conformers present in individual AD cases as an underlying mechanism behind the phenotypic variations of AD and progressive loss of synapses.
To investigate the diversity of tau propagation and associated synaptic toxicity of distinct tau conformers, we apply neuronal cell models such as primary neurons, differentiated SH-SY5Y cells, and iPSC-derived neurons. By conformational-sensitive immunoassays and fluorescent microscopy, we analyze the accumulation rate, tau isoform ratio, and conformational characteristics of de novo-induced tau aggregates. Moreover, the dynamics of synaptic maintenance and their loss are evaluated using a panel of pre-and post-synaptic markers.
Different AD tau isolates induced different rates of accumulation of predominantly 4-repeat tau aggregates in primary neurons that demonstrated distinct conformational characteristics corresponding to the original AD brain tau. The time-course of the formation of misfolded tau and colocalization correlated with significant loss of synapses in tau-inoculated cultures and the reduction of synaptic connections implicated the disruption of postsynaptic compartment as an early event. These and previous biophysical data argue for an ensemble of various misfolded tau aggregates in individual AD brains and template propagation of their homologous conformations in neurons with different rates. Modeling tau aggregation in neuronal cell models provides a useful cell-based platform to deeper investigate divergent molecular mechanisms of tau strain propagation and synaptic dysfunction. Identification of common structural features of misfolded tau and critical interactors should reveal the new therapeutic targets and approaches in AD.