By Robert Gonzales, io9.com, September 6, 2012
In recent years, some of the haze obscuring neuroscience's view of Aβ peptides and their role in Alzheimer's has lifted, as researchers uncover more and more evidence that these small protein chains play a causative, neurologically harmful role in the disease. They've been found to disrupt communication between neurons, and have been implicated in toxic cell-signaling events that can lead to everything from inflammation, to mitochondrial dysfunction, to cell death. Yet the various cellular mechanisms by which these peptides bring about such destructive outcomes remains muddled.
In today’s issue of Neuron, a team of researchers led by Ohio State University biochemist Sung Ok Yoon have opened a new therapeutic door for Alzheimer's research by shedding valuable light on the cell-signaling pathways of Aβ42, the form of Aβ-peptide most likely to clump into Alzheimer's hallmark plaques. In doing so, the researchers discovered that deleting an enzyme known as JNK3 from the genes of mice with a model form of Alzheimer's lowered Aβ-peptide production by 90 percent over the course of six months.
The molecular players involved in the pathway are numerous, and the details of their dance — while not overly complex — are too lengthy to include here, so here's a distilled version:
JNK3 activation model via Yoon et al.
Yoon and her colleagues show that Aβ42 blocks the production of a variety of proteins, and that this "translational block" triggers a cellular stress reaction known as the unfolded protein response, or UFR. UFR gives rise to a whole mess of cellular activity, including the activation of JNK3.
JNK3's activity in the brain is typically low, but is thought to spike in response to things like stress and illness. One of JNK3's job is to label Amyloid Precursor Protein (which, as its name implies, is a precursor to Aβ42) for processing into Aβ42 and other Aβ-peptides; if this precursor isn't tagged, Aβ42 has a harder time getting made. It follows, then, that when JNK activity is high, Aβ-peptide production increases, too. Or, as Yoon writes:
"JNK3 activation, which is increased [in human cases of Alzheimer's disease] and [mouse models of Alzheimer's disease], is integral to perpetuating Aβ42 production."
This process, hypothesizes Yoon, leads to a destructive feedback loop. "Around and around and around it goes, ever more strongly," she explained in a press release. "These results suggest that JNK3 is the key perpetuating the cycle."
So what happens when you remove JNK3 from the picture? A few things. As we mentioned earlier, it led to a 90% drop in Aβ42 levels among disease-affected mice. But it also results in a dramatic reduction of overall plaque loads, increased total neuronal number and even improved cognition.
Alzheimer's mice with missing JNK3 reached cognitive functions 80% that of normal; in disease model mice, function was limited to 40% of normal.
According to Yoon, the mice used for the study are models for the most aggressive form of Alzheimer's Disease, producing the highest amount of Aβ-peptides; and the 90% drop is the biggest in Aβ-peptide levels "that has been reported so far by treating animal models with drugs or genetic manipulations."
"The fact that we found that protein synthesis is hugely affected by Alzheimer's disease opens up a door to let us try a variety of drugs that are already developed for other chronic progressive diseases that share this commonality of affected protein production," Yoon said.
The researchers' findings are published in the latest issue of Neuron.