Alzheimer’s Disease is a devastating neurodegenerative disease with increased impact on the world’s ageing population and several studies have suggested that there is increased incidence in women. https://www.health.harvard.edu/blog/why-are-women-more-likely-to-develop-alzheimers-disease-202201202672. There is, therefore, considerable interest in developing more effective treatments, through better understanding of the underlying causes.
A hallmark of Alzheimer’s Disease is the presence of amyloid plaques in patients’ brains. We know that these plaques contain aggregated Aβ, the abnormal cleavage product of the Amyloid Precursor Protein (APP). A central question is whether Aβ causes degeneration of neurons long before it makes plaques.
To address this challenge, collaborating researchers from Oxford (UK) and Taipei (Taiwan) have identified a cell in fruit flies with exceptionally large secretory compartments, which are involved in APP cleavage and Aβ release, so these events can be followed in living cells for the first time. This approach has revealed that APP and associated membranes control normal protein aggregation, which is disrupted by Aβ, resulting in secretory compartments being targeted for breakdown and recycling. These defects are compounded by a breakdown in the recycling machinery, leading to the secretion and abnormal uptake of aggregating proteins by other cells, spreading the pathology. These changes mirror early events associated with neurodegeneration in brain tissue of Alzheimer’s Disease patients.
‘Our data suggests that abnormal interactions between APP, membranes and protein aggregates may be an early trigger for the cellular events leading to neurodegeneration’, says Prof Clive Wilson (DPAG), whose group led the fly research in this study. ‘What has been missing until now is a way of following the pathology as it emerges and finding the mechanisms involved. Our findings help to explain several observations relating to Alzheimer’s that have been difficult to rationalise previously.’
Ongoing research suggests other major players in Alzheimer’s, like the cytoskeletal protein tau, can also disrupt the same protein aggregation process, suggesting that defects in this process may be driving pathology. ‘We have identified treatments in flies, which suppress the Aβ-and tau-induced defects’, says one of the lead researchers involved in this project, Dr Bhavna Verma (DPAG), ‘and we are now using other fly models of Alzheimer’s to determine whether they block degeneration.’
‘We’ve found that these fundamental cellular mechanisms, linking membranes and protein aggregates, may also go awry in diseases such as cancer and reproductive disorders, like pre-eclampsia’, added Prof Deborah Goberdhan (NDWRH), whose team in Oxford discovered several of the key parallels between fly and human secretory compartments, ‘so we’re hopeful that our combined fly and human approach will generate new ideas for therapeutics and diagnostics relevant to these diseases, as it is starting to do for Alzheimer’s.’
With women at higher risk of Alzheimer’s and the global impact of neurodegeneration rising with ageing populations, understanding these fundamental mechanisms could be crucial in developing more effective treatments.
The full paper, Expression of the Alzheimer’s-associated Aβ-peptide disrupts the normal aggregation of proteins in secretory compartments, is available in the EMBO Journal .