Alzheimer’s is slowly giving up its secrets – and ‘risk genes’ are just one piece of the puzzle3 September 2018
September is World Alzheimer’s Month – an annual international campaign to raise awareness and challenge the stigma that surrounds dementia. Here, Anna Burt (School of Medicine) tells us how researchers are using genetic information to piece together our understanding of the disease.
Although the causes of Alzheimer’s disease remain a mystery, genetic research is now providing clues about how the disease develops. We know that rare genetic mutations can cause early-onset Alzheimer’s, however, both genetic and environmental factors are involved in the more common, late-onset form of the disease. By collecting information on the genetic make-up of thousands of people, scientists in our group, and others, have identified nearly 30 gene variants that are more common in the disease.
The function of many of these “risk genes” in the brain is unknown, but they appear to cluster by biological function, giving us greater insight into the mechanisms involved in Alzheimer’s. One of the biological functions implicated in Alzheimer’s from these genetic findings is the transport of material into the cell, known as endocytosis. This occurs when material cannot passively cross the cell membrane, the cell buds inwards to capture the cargo in a small fluid-filled sac.
Our research group is investigating what these endocytic genes do in the brain. Using cells grown in a dish, we can manipulate the proteins they express and measure changes in the uptake of material by the cell. This helps us to understand what happens when these genes are impaired in Alzheimer’s.
Endocytosis is a universally important cell function, all cells need to eat and drink. It is also responsible for many other vital tasks including communication, transport and cleaning up waste products, such as beta-amyloid. This is a protein produced in the healthy brain which is normally broken down and eliminated. In Alzheimer’s disease, however, it is thought that an imbalance of beta-amyloid production and its removal from the brain causes a build-up and the formation of sticky clumps, known as plaques, which are toxic to neurons.
Mopping up beta-amyloid is one of the functions carried out by microglia, the immune cells of the brain. They are the first responders when an intruder enters the brain. They use their endocytic abilities to engulf and destroy waste material and infectious agents. In Alzheimer’s, this function is key as they consume beta-amyloid, breaking it down through their internal waste-disposal system.
Beta-amyloid can also be removed via the 650km of blood vessels throughout the human brain. The endothelial cells lining the vessels form a tight barrier between the blood and the brain. This stops toxic agents but allows nutrients to enter and waste products to escape. Beta-amyloid is removed from the brain by a special form of endocytosis that involves it binding to a receptor on the surface of endothelial cells, like a lock and key. This triggers its internalisation and it is carried across the cell and deposited in the blood, preventing a build-up in the brain.
How does beta-amyloid get there in the first place?
The precise function of beta-amyloid is still unclear, but it is likely that it plays a role in normal brain physiology, only becoming a problem when present in excess. It is produced by the breakdown of the amyloid precursor protein (APP), found on the surface of cells in the brain.
APP can be broken down in two different ways, only one of which produces beta-amyloid. The enzyme responsible for this pathway resides inside the cell, so APP must undergo endocytosis in order to be broken into beta-amyloid fragments.
Part of our research involves measuring the amount of beta-amyloid and other fragments produced by cells as a result of APP breakdown. Comparing these between healthy cells and those where Alzheimer’s risk genes have been manipulated allows us to understand the involvement of these genes in beta-amyloid production. Here, again, endocytosis appears as a crucial player in the potential development of Alzheimer’s disease.
This illustrates just three examples of how endocytosis is important for brain health and how a fault in any of these could be a contributory factor to Alzheimer’s development. Indeed, many other biological processes have been implicated from genetic studies and these are unlikely to be mutually exclusive. With the addition of both lifestyle and environmental risk factors, Alzheimer’s is highly complex. Nonetheless, by understanding the various mechanisms involved, we can begin to identify potential targets for treatment. Much like a jigsaw puzzle, we are using genetic information as corner pieces to build up a clearer picture of the disease as a whole.