Investigating how ageing contributes to tauopathy: implications for Alzheimer’s Disease

Abstract

Age is the single biggest risk factor for Alzheimer’s Disease (AD). It is currently unclear how cellular changes that occur during ageing predispose people to the formation of the tau and Aβ pathologies found in AD. Recently, the same cellular pathways that are implicated in ageing have also been found to be altered in AD. These pathways include those involved in the maintenance of protein turnover such as mTORC1 signalling and autophagy. To understand how ageing contributes to the risk of developing AD we sought to analyse how these pathways change with age and how they can impact on the tau pathology found in AD.

To initially understand age-related changes in tau, different tau isoforms of human tau were expressed in Drosophila to assess age-related changes in tau-mediated phenotypes and pathologies. Htau0N3R expression caused reduced lifespan and deficits in age-related climbing ability compared with controls. Htau0N4R induced less severe effects on both longevity and climbing than htau0N3R flies. Specific phosphorylation sites were also found to be altered, with age, in htau0N3R but not in htau0N4R flies, implicating phosphorylation in age-related phenotypes. Both isoforms of htau were found to accumulate with age, suggesting dysfunction in pathways that regulate protein turnover. In addition, htau0N3R flies were assessed for changes in circadian rhythms. Expression of htau0N3R in the central clock neurons induced slowing of the circadian clock. htau0N3R was also demonstrated to induce deficits in short term memory tested using a new high throughput adaptation of a learning and memory assay.

To understand how pathways involved in regulation of protein turnover are altered in normal ageing, components of both mTORC1 signalling and autophagy pathways were assessed biochemically for age-related changes in human cortical brain tissue resected from differently aged patients undergoing neurosurgery. The mTORC1 signalling pathway was found to be less active with age and this was correlated with increased levels of autophagy and reduced total and phospho tau levels. Genetic up-regulation of autophagy in htau0N3R Drosophila similarly resulted in reduced deficits in locomotion and memory, together with reduced age-related accumulation of total and phospho htau0N3R protein. These studies demonstrate the importance of pathways that regulate protein turnover, such as mTORC1 signalling and autophagy, in both ageing and disease. Understanding how these pathways become dysregulated in disease has the potential to lead to new therapeutic targets for AD.

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