Raised Levels of Amyloid-β in the Retina Impair Lysosomal Function

Lysosomes recycle unwanted and damaged molecules in the cell, and are thus vital to cell health. Unfortunately, lysosomal function is progressively impaired with age. This occurs as a result of the buildup of various persistent metabolic byproducts, particularly in long-lived cells such as those of the central nervous system. Much of the research on this topic is focused on the impact of lipofuscin, but, as noted in the materials here, other forms of metabolic waste can also negatively impact lysosomal function. This loss of function contributes to age-related conditions, such as the retinal degeneration discussed here.

Amyloid beta (Ab) proteins are the primary driver of Alzheimer's disease but also begin to collect in the retina as people get older. Donor eyes from patients who suffered from age-related macular degeneration (AMD), the most common cause of blindness amongst adults in the UK, have been shown to contain high levels of Ab in their retinas.

A new study builds on previous research which shows that Ab collects around a cell layer called the retinal pigment epithelium (RPE), to establish what damage these toxic proteins cause RPE cells. The research team exposed RPE cells of normal mouse eyes and in culture to Ab. The mouse model enabled the team to look at the effect the protein has in living eye tissue, using non-invasive imaging techniques that are used in ophthalmology clinics. Their findings showed that the mouse eyes developed retinal pathology that was strikingly similar to AMD in humans.

The investigators also used the cell models, which further reduced the use of mice in these experiments, to show that the toxic Ab proteins entered RPE cells and rapidly collected in lysosomes, the waste disposal system for the cells. Whilst the cells performed their usual function of increasing enzymes within lysosomes to break down this unwanted cargo, the study found that around 85% of Ab still remained within lysosomes, meaning that over time the toxic molecules would continue to accumulate inside RPE cells. Furthermore, the researchers discovered that once lysosomes had been invaded by Ab, around 20 percent fewer lysosomes were available to breakdown photoreceptor outer segments, a role they routinely perform as part of the daily visual cycle.

Link: https://www.southampton.ac.uk/news/2021/03/amd-amyloid-beta.page


Any updates on Covalent's catabolic antibody approach to removing amyloid?

Posted by: jimofoz at March 17th, 2021 3:32 PM

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