Alzheimer disease belongs to the group of proteinopathies; it is characterized by deposition of the peptide amyloid-β (Aβ) as amyloid plaques and of the protein tau as neurofibrillary tangles
Aβ neurotoxicity is attributable to specific types of Aβ, generated as a consequence of proteolytic cleavage and post-translational modifications, which are susceptible to aggregation into different assembly states
Similar to Aβ, tau exists as multiple brain isoforms that undergo aggregation and is subject to a host of post-translational modifications, including phosphorylation and acetylation
Impairment of multiple cellular functions by Aβ and tau has been demonstrated in cellular and transgenic models, and crosstalk between these molecules has been demonstrated, particularly at the synapse
Assessment of Aβ and tau pathology is being facilitated by increasingly sensitive methods, which have clinical relevance in diagnosis and in the validation of therapeutic interventions in disease
A prerequisite for personalized medicine is the identification of distinct Aβ and tau species that are suitable for use as biomarkers in cerebrospinal fluid, blood, urine and saliva
Most neurodegenerative diseases are proteinopathies, which are characterized by the aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid-β (Aβ) and the protein tau aggregate to form plaques and tangles, respectively, which comprise the histopathological hallmarks of this disease. This Review discusses the complexity of Aβ biogenesis, trafficking, post-translational modifications and aggregation states. Tau and its various isoforms, which are subject to a vast array of post-translational modifications, are also explored. The methodological advances that revealed this complexity are described. Finally, the toxic effects of distinct species of tau and Aβ are discussed, as well as the concept of protein 'strains', and how this knowledge can facilitate the development of early disease biomarkers for stratifying patients and validating new therapies. By targeting distinct species of Aβ and tau for therapeutic intervention, the way might be paved for personalized medicine and more-targeted treatment strategies.
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J.G. is supported by the Estate of Clem Jones AO, the Australian Research Council (grant DP160103812) and the National Health and Medical Research Council of Australia (NHMRC; grants GNT1037746 and GNT1127999). F.A.M. is supported by the Australian Research Council (grants DP170100125, LE0882864 and LE130100078) and the NHMRC (grant GNT1058769 and NHMRC Senior Research Fellowship GNT1060075). L.-G.B. is supported by the Peter Hilton Fellowship. The authors thank R. Tweedale for critically reading the manuscript.
The authors declare no competing financial interests.
- Long-term potentiation
A cellular mechanism underlying learning and memory that involves a persistent increase in synaptic strength following high-frequency stimulation.
A post-translational modification involving conjugation with small ubiquitin-like modifiers (SUMOs).
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Polanco, J., Li, C., Bodea, L. et al. Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies. Nat Rev Neurol 14, 22–39 (2018). https://doi.org/10.1038/nrneurol.2017.162
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