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Activate or inhibit? Implications of autophagy modulation as a therapeutic strategy for Alzheimer’s disease

Krishnan, S., Shrestha, Y., Jayatunga, D.P.W., Rea, S., Martins, R. and Bharadwaj, P. (2020) Activate or inhibit? Implications of autophagy modulation as a therapeutic strategy for Alzheimer’s disease. International Journal of Molecular Sciences, 21 (18). Article 6739.

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Abstract

Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer’s disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment.

Item Type: Journal Article
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: MDPI
Copyright: © 2020 by the authors
URI: http://researchrepository.murdoch.edu.au/id/eprint/57722
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