What do we know:
Alzheimer’s disease is the leading cause of dementia and can be inherited through changes in a gene called PS1. These changes makes it hard for neurons and other cells to get rid of their waste, and make the cells less healthy.
What don’t we know: We don’t know how these changes in the PS1 gene impairs waste recycling in cells.
What this study shows: In cells from patients who have changes in PS1, the part of the cell responsible for recycling is not as acidic as normal recycling centers, making them less effective. If you make these recycling cell parts more acidic in PS1 cells, they regain their function.
What we can do in the future because of this study: We have more information on what is going wrong in the messed up PS1 neurons and can use this information to develop therapy for Alzheimer’s patients.
Why you should care: Alzheimer’s disease currently has no cure and is increasingly common among the elderly. By figuring out what goes wrong in the cells of Alzheimer’s patients, we can find potential ways to treat it.
There is a mutation in a gene called presenilin 1 (PS1) that is one of the leading causes of familial Alzheimer’s disease. This mutation in PS1 makes it hard for cells to clear their waste and recycle these molecules to stay healthy. The major “waste facility” of the cell is an organelle called the lysosome. When the lysosome becomes less acidic than normal, it struggles to clear and recycle the waste building up in the cell. This study explored whether there is a change in acidity in the lysosome in cells with the PS1 mutation. Using a new and very sensitive technique to measure acidity changes in the lysosomes of the skin cells in patients with the PS1 mutation and in healthy controls, the researchers were able to see that the PS1 lysosomes were less acidic than healthy lysosomes. This reduction in acidity was shown to impair the lysosome’s ability to recycle and breakdown waste products. The scientists then used a molecule called cAMP to restore the typical acidity in the PS1 lysosomes, and this helped to improve the function of the lysosomes in taking care of the waste products. The researchers suggest that this might be a new way of treating Alzheimer’s disease in patients with the PS1 mutation.
Impairments in autophagy in neurons is characteristic of many neurodegenerative diseases, including Alzheimer’s disease. A transmembrane protein in the lysosome called presenilin 1 (PS1) is one of the most common mutations in early-onset Alzheimer’s. The mutation in PS1 creates autophagy pathology and leads to buildup of amyloid beta, but the mechanism behind this pathology is not well understood. Using a novel technique to measure subtle pH differences in the lysosome, the authors examined the lysosomal pH found in skin fibroblasts of PS1 patients and found a slight alkalization of lysosomal pH previously undetectable with other measurements of intracellular pH. The expression levels of both mRNA and protein for genes involved in autophagy were shown to be increased in the PS1 fibroblasts, suggesting that a lysosomal pH compensation mechanism may explain the delay in pathology of a PS1 mutation. In particular, lysosomal alkalization impaired the maturation process of cathespin D, a lysosomal protease. The authors introduced cAMP to the PS1 fibroblasts to re-acidify lysosomal pH, resulting in partial rescue of cathepsin D maturation and autophagic function. This suggests that cAMP or another small molecule may acidify lysosomal pH and serve as an avenue for treatment of early-onset Alzheimer’s disease caused by PS1 mutation.