期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 64, 期 -, 页码 S517-S527出版社
IOS PRESS
DOI: 10.3233/JAD-179907
关键词
Alzheimer's disease; amyloid; axon initial segment; focused ultrasound; fyn kinase; microtubule-associated protein tau; non-invasive; phosphorylation; spreading; vaccination
资金
- Estate of Dr Clem Jones AO
- State Government of Queensland
- Federal Government of Australia [ACT900116]
- Australian Research Council [DP160103812]
- National Health and Medical Research Council of Australia [GNT1127999, GNT1037746]
- Yulgilbar Foundation
Accumulation of the peptide amyloid-beta (A beta) 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 A beta 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 newtreatment modality to clear pathological A beta 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.
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