934C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Aarya Vaikakkara Chithran ¹; Ben Batchelor ²; Benjamin Boehme ¹; Lovesha Sivanantharajah ³; Tianshun Lian ¹; Brad Richardson ²; Eva Ruiz ²; Efthimios Skoulakis ⁴; Amrit Mudher ²; Douglas Allan ¹

Affiliations:
1) Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada; 2) Department of Biological Sciences, University of Southampton, Southampton, United Kingdom; 3) Department of Biological Sciences, University of Bangor, Bangor, United Kingdom; 4) Biomedical Sciences Research Centre, Alexander Fleming Institute, Athens, Greece

Keywords:
a. neural degeneration; a. neural degeneration

Prion-like propagation through circuits is believed to be the mechanism by which tau pathology spreads throughout the brain in tauopathies like Alzheimer's disease (AD). This is reflected in the neuropathological Braak-staging of disease and manifests in the progressive cognitive decline evident clinically. Though various synaptic proteins are implicated, the precise players and mechanism(s) mediating the trans-cellular spread of pathological tau species remain unclear. Furthermore, though the trans-cellular spread of pathological tau species has been demonstrated in many experimental models, the neurobiological consequences in recipient neurons are largely unknown. Moreover, in all such studies, the tau species that propagates is invariably mutated or isolated from pathological fractions of brains of tauopathy patients. This is puzzling given that it is wild-type tau that becomes pathological and spreads in AD, and this process is accompanied by neurodegeneration. We report a novel Drosophila model in which wildtype human tau expressed in select neuronal subsets becomes pathological and undergoes trans-cellular spread through adult brain circuits, causing neurodegeneration reminiscent of late stages of disease in AD brain. The superior genetic tractability of this model makes it ideally suited for dissection of the key players that mediate this pathogenic process through genetic and pharmacological modifier screens. Furthermore, the availability of functional and behavioural assays for many adult brain circuits will enable future studies to reveal the neurobiological consequences of spreading tau pathology more directly.