Is Neurodegeneration Due to Amyloid-β or Proteins that Accumulate With Amyloid-β?
Researchers here find a novel way to question the role of misfolded amyloid-β in the development of Alzheimer's disease. Evidence to date continues to suggest that the accumulation of amyloid-β in the aging brain is necessary to set the stage for later, more severe pathology driven by inflammation and tau aggregation. The failure of amyloid-β clearance to much modify the later disease state indicates that amyloid-β becomes less relevant as the condition progresses. But is it really the amyloid-β? Or is amyloid-β aggregation only coincident with the actual pathological mechanisms? A number of groups have proposed inflammation or infection driven models of Alzheimer's disease in which amyloid-β aggregation is a side-effect. Here researchers propose that amyloid-β aggregation allows other, potentially pathological molecules to aggregate alongside it.
In the brains of those who suffer from Alzheimer's, amyloids accumulate and build up into sticky plaque that disrupts brain functions and causes cognitive decline. The big unknown has been exactly how that occurs. According to the most widely adopted hypothesis, the amyloid beta buildup disrupts cell-to-cell communication and activates immune cells in a process that eventually destroys brain cells.
Researchers now present a new hypothesis, emphasizing a different role for amyloid beta, a simple protein that forms in all brains but normally dissolves out by natural processes. In experiments, they used cutting-edge analytical technologies to identify and measure the level of more than 8,000 proteins in human brains with Alzheimer's, as well as similar proteins in mice. Focusing on proteins whose levels increased most dramatically, they identified more than 20 proteins that co-accumulate with amyloid beta in both the human brains with Alzheimer's and the mice. As the research continues, they suspect they'll find more.
"Once we identified these new proteins, we wanted to know whether they were merely markers of Alzheimer's or if they could actually alter the disease's deadly pathology. To answer that, we focused on two proteins, midkine and pleiotrophin. Our research showed they accelerated amyloid aggregation both in the test tube and in mice. In other words, these additional proteins may play an important role in the process that leads to brain damage rather than the amyloid itself. This suggests they might be a basis for new therapies for this terrible brain affliction that's been frustratingly resistant to treatment over the years."
Link: https://news.emory.edu/stories/2024/08/hs_alzheimers_12_08_2024/story.html