Scientists have discovered that certain antibodies may help slow the progression of Alzheimer’s disease. Dr. Patricia Salinas of University College London, UK, and her team focused on a protein called Dkk1, present in raised levels in the brains of people with Alzheimer’s disease.
Using brain samples from mice, the team looked at the progressive disintegration of synapses in the hippocampus when exposed to a protein called amyloid-beta, thought to be central to the development of Alzheimer’s disease.
“Synaptic loss mediated by amyloid-beta in early stages of the disease might contribute to cognitive impairments,” explain the experts. “However, little is known about the mechanism by which amyloid-beta induces the loss of synapses.”
Tests showed that Dkk1 is linked to abnormal deposits, or plaques, of amyloid-beta, triggering the loss of synapses, the connections between neurons. Laboratory tests showed that amyloid-beta causes greater production of Dkk1.
Further tests indicated that antibodies which block the function of Dkk1 can suppress this toxic effect of amyloid-beta. The hippocampus, a brain area associated with learning and memory, is in turn protected.
The findings are published in the Journal of Neuroscience. Dr. Salinas says, “Despite significant advances in understanding the molecular mechanisms involved in Alzheimer’s disease, no effective treatment is currently available to stop the progression of this devastating disease.
“These novel findings raise the possibility that targeting this secreted Dkk1 protein could offer an effective treatment to protect synapses against the toxic effect of amyloid-beta. Importantly, these results raise the hope for a treatment and perhaps the prevention of cognitive decline early in Alzheimer’s disease.”
Dr. Simon Ridley of the study’s funders, Alzheimer’s Research UK, commented, “We’re delighted to have supported this study, which sheds new light on the processes that occur as Alzheimer’s develops. By understanding what happens in the brain during Alzheimer’s, we stand a better chance of developing new treatments that could make a real difference to people with the disease.
“Studies like this are an essential part of that process, but more work is needed if we are to take these results from the lab bench to the clinic. Dementia can only be defeated through research, and with the numbers of people affected by the condition soaring, we urgently need to invest in research now.”
Dkk1 is described as a “Wnt antagonist,” that is, it blocks the Wnt signaling pathways. These pathways regulate many essential processes, and mutations in the pathways have been linked to a range of diseases including breast and prostate cancer and type II diabetes.
Because Dkk1 is present in higher levels in brains of Alzheimer’s patients, researchers believe that problems with Wnt signaling could contribute to the disease.
The role of Wnt signaling in neural development has long been understood. But in recent years, several studies have suggested that faulty Wnt signaling is involved in degenerative and inflammatory disorders of the central nervous system, including Alzheimer’s.
A team from King’s College London, UK, investigated the way in which amyloid-beta causes Alzheimer’s. They say, “Although the mechanism of amyloid-beta action in the pathogenesis of Alzheimer’s disease has remained elusive, it is known to increase the expression of the antagonist of wnt signalling, Dkk1.”
In tests on mice, they identified a molecular pathway in which amyloid-beta boosts the expression of several genes known to be linked to Alzheimer’s. This finding provides “new mechanistic insights into the action of amyloid-beta in neurodegenerative diseases,” they write in the journal Molecular Psychiatry.
In the light of these new findings, it is possible that drugs targeted at rebalancing the “tightly regulated” Wnt signaling pathway may eventually be a useful therapeutic strategy for Alzheimer’s disease.
Dr. Erin Scott and Dr. Darrell Brann of Georgia Health Sciences University, Augusta, GA, suggest one possible avenue of therapy. In the journal Brain Research they write: “Estradiol is an endogenous steroid hormone that is well known to exert neuroprotection.”
Estradiol, the main form of estrogen in the body, protects the hippocampus from lack of oxygen by stopping levels of Dkk1 getting too high and encouraging healthy Wnt signaling in the hippocampus’ neurons.
The experts warn that this balance could be disrupted when individuals receive treatment that either reduces estrogen levels, such as some types of breast cancer therapy, or increases their estrogen levels, such as hormone replacement therapy.
In fact, the loss of estradiol that occurs naturally in women at menopause is known to lead to a raised risk of cognitive decline. But surprisingly, several clinical trials have found a detrimental effect of estrogen therapy after menopause, including increased stroke risk and dementia.
Dr. Derek Schreihofer of the University of North Texas Health Science Center at Fort Worth, TX, analysed these trials and discovered a “critical period” in which estrogen therapy must begin soon after the loss of natural estrogen production, or it will not have a beneficial effect.
It may be that these findings on estrogen and antibodies to block Dkk1 are of use in the future development of effective therapies for the treatment or prevention of Alzheimer’s disease.
Salinas, P. et al. The Secreted Wnt antagonist Dickkopf-1 is required for Amyloid B-mediated synaptic loss. The Journal of Neuroscience, March 7, 2012.
Killick, R. et al. Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Molecular Psychiatry, November 20, 2012.
Scott, E. L. and Brann, D. W. Estrogen regulation of Dkk1 and Wnt/beta-Catenin signaling in neurodegenerative disease. Brain Research, 19 December 2012.
Schreihofer, D. A. and Ma, Y. Estrogen receptors and ischemic neuroprotection: Who, what, where and when? Brain Research, 13 March 2013.
Collingwood, J. (2013). Could Antibodies or Hormones Slow Brain Damage from Alzheimer’s?. Psych Central. Retrieved on March 10, 2014, from http://psychcentral.com/lib/could-antibodies-or-hormones-slow-brain-damage-from-alzheimers/00016539
Last reviewed: By John M. Grohol, Psy.D. on 1 Jun 2013
Published on PsychCentral.com. All rights reserved.