Despite decades of research, the direct cause of brain damage in Alzheimer’s disease remains unknown, but a research team led by Emory University in the US may finally have discovered why.
Although now controversial, much of the research has focused on naturally occurring abnormal clumps of protein, or amyloid-beta plaques, that build up in the brain as Alzheimer’s disease progresses. Naturally, this prompted scientists to investigate whether plaques play a role in brain cell damage.
But other researchers now argue that these plaques may be a side effect, rather than a cause, of Alzheimer’s, for a variety of reasons. First, laboratory studies have shown that plaques do not directly damage brain cells. Treatments targeting these proteins have also not been as successful as hoped, suggesting that a key component of the disease has yet to be found.
The latest findings seem to support this missing element idea.
Emory University biochemists Yona Levites and Eric Dummer and their colleagues have found evidence that other proteins that build up along with plaques may be responsible for the terrible symptoms of Alzheimer’s.
The amyloid-beta clumps act as scaffolding to attract other molecules, which can lead to dire symptoms like confusion, communication problems and memory loss.
The team compared protein combinations in a mouse model of Alzheimer’s disease over time with data from humans, some of whom had Alzheimer’s disease and some of whom had plaques in their brains but no symptoms of the disease.
They identified more than 20 proteins that accumulate alongside amyloid-beta in both mice and humans.
Many of these proteins are signaling molecules, but when they get stuck in plaques, they can send signals in the wrong place, activating processes that don’t belong there.
“In other words, these additional proteins, rather than the amyloid itself, may play a key role in the processes that lead to brain damage,” explains biochemist Todd Gold of Emory University.
“After identifying these new proteins, we wanted to know whether they were simply markers of Alzheimer’s or whether they could actually alter the deadly pathology of the disease.”
By mapping different combinations of these molecules, a pattern emerged: The researchers found that the buildup of amyloid-beta plaques was accompanied by overexpression of two other proteins, midkine and pleiotrophin, both of which are involved in inflammatory processes in the body.
“This suggests that this could be the basis for new therapies for this terrible brain disease that has been difficult to treat for many years,” Gold said.
Using amyloid as a scaffold may better explain some of the contradictory results that have emerged in recent studies, and the team explain that under normal circumstances, amyloid’s natural function is in part to act as a scaffold for other mechanisms.
Although the roles of many of these other proteins still need to be investigated, initial testing of midkine and pleiotrophin in the laboratory has revealed that these molecules accelerate plaque formation.
“It is important to consider that the accumulation of proteins in plaques is not simply a bystander effect, but is part of a response to amyloid as a danger-associated molecular pattern,” Levites and his colleagues wrote in their paper.
“Many of the proteins that interact with amyloid may be involved in removing, coating, neutralizing, or a combination of these structures to reduce toxicity.”
This may explain why amyloid-β protein may or may not be involved in neuronal damage in some way: it may depend on what other molecules are present.
However, there are some possible theories that have not yet been ruled out, such as the theory that Alzheimer’s is an autoimmune disease.
“The study reveals a highly complex set of changes that occur in an individual’s brain over decades as Alzheimer’s disease pathology emerges,” the researchers note.
Their study was published in Cell Reports Medicine.