Alzheimer’s Plaques Co-Accumulate with Potential Biomarker or Target Proteins

Amyloid beta deposits long known to build up in the brains of Alzheimer’s disease (AD) patients have been found to serve as a kind of scaffold for the accumulation of other proteins. Because many of these proteins have known signaling functions, their presence around the amyloid accumulations, known as plaques, could be the culprit causing brain cell damage rather than the amyloid itself.

This finding, from Emory University scientists, was described August 9 in Cell Reports Medicine, in an article titled, “Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer’s disease.”

“[We] compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome,” the article’s authors wrote. “Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid, and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk), and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA.

“M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets.

In the brains of those who suffer from Alzheimer’s, amyloid beta is known to form sticky plaque that is associated with disrupted brain functions and cognitive decline. However, mechanistic details have remained unclear. 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.

In the new study, which presents work that was led by Todd E. Golde, MD, PhD, director of the Emory Center for Neurodegenerative Disease in the Goizueta Institute, a new hypothesis is suggested. A different role is proposed for amyloid beta, a simple protein that forms in all brains but normally dissolves out by natural processes.

Golde’s team 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,” Golde said. “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.”

While the basics of Alzheimer’s have been understood for more than a century, the search for a cure has been slow, often marked by repeated cycles of initially promising treatments that didn’t work in trials, as well as continuing controversy over competing theories to best explain how the disease damages the brain. As the researchers put it, “The initial notion of a purely linear amyloid cascade is now recognized as simplistic. Multi-omic studies have unveiled the vast complexity of changes occurring over decades in the brains of individuals as Alzheimer’s pathologies emerge.”

Significantly, multiple kinds of amyloid buildup, besides amyloid beta, have been implicated in more than 30 human disorders affecting tissues and organs throughout the body. Because this new research proposes a novel process by which Alzheimer’s develops, it may allow for fresh approaches to discovering treatment targets for other diseases as well.