Axonal transport defects in Alzheimer's disease and related disorders: mechanisms of tau pathology
Alzheimer’s disease (AD) is characterized by two types of insoluble protein deposits in the brain, tau-containing neurofibrillary tangles and β-amyloid (Aβ)-containing plaques. Although axonal transport has been proposed as a potential pathomechanism of tau, the precise sequence of the cellular events that underlie such tau-dependent transport defects are only poorly understood. Due to the complexity of real-time analysis of neuronal functions in intact behaving mouse models, most research into the role of tau in axonal transport involves the use of cultured cells. However, these experimental systems fail to reproduce the complex cellular and systemic influences that determine cellular functions in vivo. The roundworm C. elegans is, however, ideally suited for these purposes due to its transparency, short life cycle, concise neuroanatomy and well-characterized genetics. Here we propose to exploit the powerful genetic tools available in C. elegans, together with advanced real-time microscopy of fluorescently labelled proteins, to gain insights into the pathological mechanisms that cause tau to impair axonal transport. Understanding the pathogenic pathways and molecular components underlying the progressive axonal transport defects in tauopathies over time will provide a framework for the development of novel therapeutic strategies.
Dr Matamales is a Postdoctoral Research Fellow based at the Queensland Brain Institute, University of Queensland.