Brain clean-up efforts promote Alzheimer's disease

Cellular garbage disposal structures, known as lysosomes, may be worsening damage caused by Alzheimer’s disease, according to researchers at Yale University School of Medicine.

More than half a million people in the UK suffer from Alzheimer's disease. Symptoms of this disease, including memory loss and communication problems, are due to a build-up in the brain of sticky protein aggregates called amyloid plaques. These damage nearby nerve cells and are a hallmark feature of the disease for which there is currently no cure. However, Yale scientist Shawn Ferguson and his team have made a striking discovery about the role of structures called "lysosomes" in the formation of these plaques.

Ferguson was intrigued by electron microscopy studies from the 1960s which showed that wherever amyloid plaques cropped up in the brain, the axons of adjacent nerve cells were often grossly swollen. Axons play an important role in the transmission of information between nerve cells and also from the brain to other parts of the body and they are normally thin and thread-like. But the abnormally-swollen axons surrounding the amyloid plaques in the Alzheimer brains were packed with sac-like structures called lysosomes. Lysosomes clean up internal debris that cells no longer require, and they're not normally found in axons. Since amyloid plaques are believed to be detrimental to the brain, Ferguson hypothesised that the presence of these lysosomes may be beneficial, possibly providing protection to the nerve cells by degrading the damaging plaque.

To determine exactly how lysosomes affect the development of amyloid plaques, the team monitored the growth of these plaques in a mouse model of Alzheimer’s disease. These are mice that have been genetically modified to possess the genes that cause Alzheimer’s disease in humans. The abundance of lysosomes surrounding the plaques was then increased in a subset of the mice by inhibiting lysosome transport within their nerve cells. The rate at which amyloid plaques cropped up within this group of mice was compared with animals without lysosome accumulations.

The results, published in the Journal of Cell Biology, were striking and show that, in complete contradiction to the beneficial role they were presumed to be playing, lysosome accumulations in nerve cells actually worsen amyloid plaques and promote Alzheimer's progression.

So, why are lysosomes unable to degrade the plaques? And why are they doing exactly the opposite of what they should be doing?

Further investigations showed that, when lysosomes accumulate, they cannot effectively degrade potentially harmful materials, like amyloid plaques. In other words, they can only get their job “half done”. This partial breakdown of the plaques generates half-digested proteins and other materials, which, paradoxically, provides the ingredients to make more amyloid plaques.

These slightly counterintuitive findings show that lysosomes do not have a beneficial function within the axons and are not merely innocent bystanders. Instead they have a detrimental effect on the progression of the disease.

“Preventing the build-up of lysosomes around these plaques would be beneficial... and [the findings] also cause us to look to other incidents in human neurons where lysosome transport may get disrupted," explains Ferguson.

Now that the detrimental effect of these lysosome accumulations has been discovered, research is investigating how insults like traumatic brain injuries can interfere with lysosome transport in nerve cells and potentially contribute to the risk of Alzheimer’s disease development.