Longevity Briefs: Engineering ‘Young Blood’ Components To Treat Alzheimer’s In Mice

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Blood plasma (the liquid component of the blood with the blood cells removed) from young animals extends lifespan and delays signs of ageing in older animals. This remarkable effect is thought to be partly the result of ‘dilution’ of harmful age-related factors in the old animal’s blood, and partly due to beneficial components in the young animal’s plasma. What are those beneficial components? It seems as though exosomes (tiny lipid-wrapped packages that cells naturally secrete to communicate with each other) may play a significant role in the benefits of so-called ‘young plasma’.

Exosomes deliver genetic material and signalling molecules to distant cells, within which they can elicit a beneficial response. Previous research has suggested that certain exosomes can improve cognitive function in mice, and there are now ongoing efforts to understand what specific components within exosomes are responsible for their benefits, as well as the possibility of engineering them further to treat age-related diseases. In this study, researchers investigate whether their own engineered exosomes could be used to treat Alzheimer’s disease in mice.

The discovery:

To produce their therapeutic exosomes, researchers first isolated human exosomes from plasma donated by healthy 18–25 year-olds. Researchers then modified these exosomes by attaching a peptide called rabies virus glycoprotein-targeting peptide (RVG-29) to their surface. As the name implies, RVG-29 comes from the rabies virus. It binds to receptors on the surface of neurons and cells that make up the lining of blood vessels in the brain, helping the virus to both penetrate the blood-brain barrier and infect neurons. By attaching RVG-29 to the surface of exosomes, researchers aimed to enhance their delivery to Alzheimer’s-affected brain tissue.

To test these exosomes, researchers first exposed human neurons to amyloid-β (the main misfolded protein implicated in Alzheimer’s disease) in order to simulate Alzheimer’s-affected neurons. They then treated these cells with either unmodified exosomes or RVG-engineered exosomes (RVG-EXOs) for 24 hours. They found that RVG-EXOs were significantly more effective at clearing toxic amyloid-β and preventing neuron death compared to unmodified exosomes, suggesting that the addition of RVG did successfully improve the effectiveness of the treatment.

Showing an effect in cells is one thing, but the real test would be whether RVG-EXOs could improve outcomes in a mouse model of Alzheimer’s disease. Researchers used a standard Alzheimer’s mouse model that rapidly develops amyloid-β and tau pathology similar to human Alzheimer’s disease. Mice were then randomly divided into four groups of 8. One group received an injection of saline solution as a control, while two groups received either unmodified exosomes or RVG-EXOs. The fourth group were normal, non-diseased mice serving as the healthy control. Injections were given 3 times a week over 4 weeks, after which the mice underwent various memory and behavioural tests. In all cases, unmodified exosomes significantly improved mouse performance compared to control treatments, while RVG-EXO-treated mice performed better still. For example, mice treated with RVG-EXOs took less time to find the location of a hidden platform under water and were better at recognising objects they hadn’t previously seen compared to mice treated with unmodified exosomes.

Finally, researchers used genetic sequencing to analyse the contents of the exosomes in order to investigate how they might be having a beneficial effect on the brain. They found that exosomes from young plasma had higher levels of certain microRNAs (small RNA molecules that regulate gene expression). These microRNAs blocked a gene that encodes a component of mTOR, a protein implicated in ageing with which readers might be familiar. Reduced mTOR activity resulted in enhanced autophagy (the cell’s ‘garbage disposal system’) allowing neurons to clear misfolded proteins like amyloid-β and tau more effectively. In support of this being a key mechanism, researchers found that genetically boosting the expression of this mTOR component in mice completely prevented the therapeutic benefits of RVG-EXOs.

The implications:

Young people don’t get Alzheimer’s disease, and so one strategy to prevent or reverse Alzheimer’s (and age-related diseases in general) is to identify what is fundamentally different about the biology of young people and reproduce that biology in older people to the fullest extent possible. The blood and the factors within are an essential aspect of the environment to which cells are constantly exposed, and one that we know changes in many ways with age. Research increasingly points to exosomes as a key component of ‘young blood’ that could have a wide range of therapeutic applications. This study suggests there is potential to engineer these exosomes for further benefits by targeting specific cells.

It is important to be aware that mice that have been genetically engineered to rapidly develop Alzheimer’s are not the same as humans who develop this disease slowly over the course of many decades. Alzheimer’s mouse models generally represent an exaggerated version of the disease in which the accumulation of Amyloid-β and other misfolded proteins may play a greater role than they do in humans. This means that a treatment that works primarily by enhancing the degradation of these proteins might not work as well in human patients.