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Molecule impairs brain cells that fail in Alzheimer's

Blocking one part of misbehaving immune cells could ease dementia symptoms

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3:30pm, December 9, 2014
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A molecule on disease-fighting cells in the brain may be responsible for their failure to clear errant proteins in people with Alzheimer’s disease, a new study finds. Removing this molecule in mice allowed their cells to gobble up the culprit proteins more efficiently, and prevented mice susceptible to Alzheimer’s from developing memory problems as they aged.

“This is a possible target that we could look at for preventing Alzheimer’s disease, or preventing progression of dementia,” says Katrin Andreasson, a coauthor of the new research, published December 8 in the Journal of Clinical Investigation.

Patrick McGeer, a neuroscientist at the University of British Columbia in Vancouver, cautions that previous treatments that ease Alzheimer’s symptoms in mice have not translated well to people. “Mouse models have been helpful, but a mouse is not a man, and too often models have led people down a false track,” he says.

In many neurodegenerative diseases such as Alzheimer’s, proteins fold into the wrong shape and build up to form a plaque in the brain. Normally, immune system cells in the brain called microglia clear out misfolded proteins. One such protein is amyloid-beta. The protein is produced when nerve cells fire, and when folded properly, may play a role in turning off synapses, where messages are transmitted from one nerve cell to another.

In Alzheimer’s, however, the immune cells are impaired. “The microglia become really dysfunctional over time,” says Andreasson, a neurologist at the Stanford University School of Medicine. “They will launch really over the top, very toxic inflammatory responses, and they will not clear the aggregating amyloid-beta.”

This abnormal immune activity damages nerve cells and somehow triggers them to produce even more amyloid beta, creating a vicious cycle of inflammation.

People with Alzheimer’s also have increased amounts of certain lipids in their spinal fluid. These lipids fasten onto a molecule called a receptor that sits on the surface of microglial cells. Andreasson and her team investigated the receptor, EP2, to see whether it plays a role in impairing microglia in people with Alzheimer’s.

First, the team exposed young and old mouse macrophages, immune cells that behave like microglia but are less fragile, to amyloid-beta. The young cells barely responded to the protein. The old macrophages, however, had more EP2 receptors and responded to the protein with more inflammation.

“It could be that these cells acquire more receptors over time,” says Andreasson, noting that the immune system deteriorates with age even in otherwise healthy people.

Next, the researchers genetically modified mice to lack EP2 receptors in their microglia. When exposed to amyloid-beta, the microglia responded with a muted inflammatory response and more efficiently cleared out the protein. In addition, immune cells without EP2 produced a protein that has previously been found to protect nerve cell synapses from deteriorating.

In another experiment, mice were modified to be more susceptible to Alzheimer’s disease as they aged. Within this group, mice without the EP2 receptor did not develop memory problems as they got older. Their synapses, which are typically damaged in Alzheimer’s, also stayed intact.

“The EP2 receptor makes everything worse,” says Andreasson. In the future, she wants to investigate how EP2 stops microglia from working in Alzheimer’s, and whether it also plays a role in other neurodegenerative diseases such as Parkinson’s.

Citations

J.U. Johansson et al. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models. Journal of Clinical Investigation. Published online December 8, 2014. doi:10.1172/JCI77487.

Further Reading

M. Rosen. Stopped brain clock saves memory in hamsters. Science News Online, November 13, 2014.

T.H. Saey. Pregnancy disorder shares aspects with Alzheimer’s. Science News. Vol.186, August 23, 2014, p.19.

S. Gaidos. The Inconstant Gardener. Science News. Vol.184, November 30, 2013, p.22.

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