Six years ago, researchers reported that dkk1 appears to be involved in the destruction of synapses in Alzheimer's disease. More recent work expands the understanding of dkk1 in this context, placing it in a positive feedback loop related to amyloid-β, in which synaptic damage drives more synaptic damage. The researchers provide evidence to suggest that dkk1 protein can be a therapeutic target for treatments that slow the progression of Alzheimer's disease. Fortunately, there is an existing approved drug that might be used to produce a proof of concept in human patients, so it seems likely that we will be hearing more from this line of research in the years ahead.
Overproduction of the protein beta-amyloid is strongly linked to development of Alzheimer's disease but many drugs targeting beta-amyloid have failed in clinical trials. Beta-amyloid attacks and destroys synapses - the connections between nerve cells in the brain - resulting in memory problems, dementia, and ultimately death. In a new study researchers found that when beta-amyloid destroys a synapse, the nerve cells make more beta-amyloid driving yet more synapses to be destroyed. "We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production. We think that once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective, and this could explain why so many Alzheimer's drug trials have failed."
The researchers also found that a protein called Dkk1, which potently stimulates production of beta-amyloid, is central to the positive feedback loop. Previous research identified Dkk1 as a central player in Alzheimer's, and while Dkk1 is barely detectable in the brains of young adults its production increases as we age. Instead of targeting beta-amyloid itself, the researchers believe targeting Dkk1 could be a better way to halt the progress of Alzheimer's disease by disrupting the vicious cycle of beta-amyloid production and synapse loss. "Importantly, our work has shown that we may already be in a position to block the feedback loop with a drug called fasudil which is already used in Japan and China for stroke. We have convincingly shown that fasudil can protect synapses and memory in animal models of Alzheimer's, and at the same time reduces the amount of beta-amyloid in the brain."