Affiliations: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane (St Lucia Campus), QLD, Australia
Correspondence:
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Correspondence to: Jürgen Götz, Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute, The University of Queensland, St Lucia (Brisbane), QLD 4072, Australia. Tel.: +61 7 334 66329; Fax: +61 7 334 66301; E-mail: j.goetz@uq.edu.au.
Abstract: Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer’s disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn. We further discuss how in a pathological state, tau, being a scaffolding protein, impairs nuclear and mitochondrial functions and reduces action potential generation at the axon initial segment. Pathological tau can further be packaged into exosomes, released by one neuron and taken up by another, contributing to its pathogenicity. We also present our new work that suggests ultrasound as a new treatment modality to clear pathological Aβ and tau. We put this work into perspective, discussing current vaccination strategies and improved brain delivery methods involving antibody engineering and viral approaches. We propose that rather than reducing post-translational modifications of tau, its levels and de novo synthesis need to be reduced. We anticipate a surge in combinatorial strategies, simultaneously targeting multiple pathologies, and an improved drug delivery to the brain facilitated by emerging technologies such as ultrasound.
