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Neurology Today:
doi: 10.1097/01.NT.0000435582.78288.e4
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Immune System Protein Identified for Age-Related Cognitive Decline

Talan, Jamie

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ARTICLE IN BRIEF

Investigators reported that the accumulation of immune system complement protein in the brain contributes to age-related cognitive decline and may also provide clues to the more severe memory and cognitive changes that occur in Alzheimer's disease and other neurodegenerative diseases.

A team of scientists at Stanford University has discovered up to a 300-fold increase in a complement protein called C1q expressed in mouse brain tissue during normal aging.

Their findings, reported in the Aug. 14 issue of the Journal of Neuroscience, show that the accumulation of this immune system protein in the brain contributes to age-related cognitive decline and may also provide clues to the more severe memory and cognitive changes that occur in Alzheimer's disease (AD) and other neurodegenerative diseases.

The investigators — led by Ben Barres, MD, PhD, professor of neurobiology, developmental biology, and neurology — are now designing molecules that target this complement protein and will be testing them to see whether they prevent age-related cognitive decline and AD.

“We knew from earlier work that C1q is produced in the post-natal period and coats the synapse and sends signals to microglial cells that mark the synapse for destruction and elimination,” said Dr. Barres. “The C1q leads to activation of another complement protein called C3 that gets deposited on the synapse. Microglia have C3 receptors that allow them to recognize and literally eat complement-coated synapses.”

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The big question was why this was happening and whether this process is turned on again later in life. Other groups had identified complement protein in the amyloid plaques in the brains of AD patients, and in animal models. These findings were thought to represent an inflammatory response. Dr. Barres and his colleagues wanted to figure out exactly why the complement cascade was activated.

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DIFFERENCES IN ANIMAL MODELS

To conduct the study, the investigators screened about 1,000 antibodies before finding one that binds to C1q only. They performed a series of studies comparing complement expression over the life of the animal. They also created transgenic C1q-knockout animals and did the same studies. Finally, they conducted a series of behavioral studies to test the effects of complement on learning and memory.

Interestingly, the complement first accumulated at synapses in areas of the brain associated with vulnerability to neurodegeneration, specifically the hippocampus, substantia nigra, and piriform cortex.

Transgenic C1q knockout mice had the same synaptic numbers as their wild type littermates but behavioral studies over the lifespan of the animals showed behavioral differences in old age. The aged C1q-deficient mice actually performed better on several behavioral tests and appeared cognitively more flexible in their response on a variety of memory tests, including the Morris Water Maze.

Younger animals with C1q on hand and the knockout animals had similar scores. The changes on the behavioral tests emerged as the animals got older.

It appears that there is “a novel function for C1q in impacting circuit diversity with aging that is independent of classical complement-mediated synaptic pruning,” the scientists wrote in the paper. “C1q has a negative effect on synaptic plasticity in the aging mice, but not in the juvenile.”

Dr. Barres said that these findings suggest that the effects are “likely due to the accumulation of C1q protein released by microglia and inhibitory neurons onto synapses.”

There were no functional abnormalities in the C1q knockout animals suggesting that the changes seen in old age were not due to changes that took place in development, he added.

Next they will try to understand “how C1q impacts the adult and aging circuitry, why C1q accumulates in close proximity to synapses, and whether this affects the aging at the synapse.” Dr. Barres said that every time the brain is injured it provides an opportunity for complement to accumulate at the synapse.

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UNDERSTANDING THE PROCESS

Scientists have suspected that inflammation in the brains of AD patients, and in animal models, were secondary to the amyloid-beta (Abeta) build-up in the brain. Abeta destroys the synapse and complement gets activated and neuroinflammation develops. But Dr. Barres and colleagues at the University of California, Irvine; University of Zurich; Howard Hughes Medical Institute; University of California, San Francisco; and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, suggest that this ordering is backward, and that the complement is activated first and that kills synapses, which are filled with amyloid precursor protein (APP).

Dr. Barres said that their idea is that microglia arrive at the scene and once they start ingesting the synapse, that converts APP to amyloid beta. The amyloid plaques may just be the remnants of this process. “We believe that the activation of complement is the earliest event in the synapse destroying process,” he said.

Dr. Barres said he suspects that the complement activation he sees in aging mice also takes place in humans. In this study the investigators looked at tissue slices from a number of human autopsied brains and showed that complement was activated in the tissue from older donors. They found an eight-fold increase of complement protein immunoreactivity in the older brain tissue.

There is evidence that activation of this complement protein is part of the normal aging process and may well be exaggerated in brains at risk for AD, Dr. Barres said. He and his colleagues founded a company in 2011 called Annexon to develop treatments that target parts of the complement cascade pathway.

“C1q is the first of many complement molecules to be triggered in response to an injury or infection,” Dr. Barres said. “It is the most abundant complement in the body. Every cell in the body has multiple molecules that strongly inhibit complement, including apolipoprotein J, so that the cells are protected while complement is fighting the infection or the injury.”

Their studies, as well as others, show that C1q sits at the synapse and gums up the machinery. The synapses don't work as well in receiving and sending signals from cell to cell. Dr. Barres said that he believes that “this is the missing link between the aging brain and vulnerability to AD.”

“Neurons have figured out a way in the normal brain to use complement,” said Dr. Barres. They now have a C1q antibody in hand so that they can test where C1q turns on in the brain and where it gets deposited.

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EXPERTS WEIGH IN

“In this work, the Barres lab shows that the protein C1q is strongly increasing in the brain of mice with aging. The idea that C1q could be involved in synaptic dysfunction with aging is suggested by this work,” said David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones professor and chairman of neurology at Washington University School of Medicine. “It is certainly conceivable that C1q is also linked with synaptic damage in AD and other neurodegenerative diseases, though this remains a hypothesis that still needs data to know for sure whether this is the case. It appears to be a very promising hypothesis.”

“As C1q can regulate processes such as phagocytosis, immune regulation, neuroprotection, and synapse elimination, it is possible that this increase during aging could influence these processes. The changes shown in this paper in regard to the increase in C1q are very strong. It leads one to now try to understand whether this large increase in C1q is functionally regulating the processes mentioned. If so, this can be a novel target for therapy. As an example, if C1q is stimulating synaptic damage/loss, then blocking the actions of C1q might decrease synaptic loss and prevent decline in memory and other cognitive functions,” he said.

Marie E. Benoit, PhD, a research scientist at Virginia Commonwealth University, studies C1q protein in the central nervous system. “This is the first study to systematically analyze C1q in the aging brain,” she said. “What is unexpected is that it seems to be only C1q and not other complement proteins. C1q does not need any other complement protein to do what it does in the aging brain,” she said. “This means that there is probably another function of C1q that we don't understand yet.”

Complement proteins have been known to take up residence in the AD brain. Huntington Potter, PhD, professor of neurology and director of the Alzheimer's Disease Program at the University of Colorado, said that it is an “interesting finding,” but not as convincing as the scientists argue. “It needs further work,” he added.

“With such a large increase in C1q, you would expect to see a much bigger effect on preventing cognitive decline in old age. The suggestion that you can knock out C1q completely and get an effect on age-related cognitive decline is a stretch,” Dr. Potter said. “It is a fascinating finding that needs further research. It would be interesting to see whether amyloid accumulation is blocked when you shut down C1q expression in aging animals at risk for AD.”

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LINK UP FOR MORE INFORMATION:

•. Stephan AH, Madison DV, Mateos JM, et al. A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci. 2013; 33:(33):13460–13474.

•. Benoit ME, Tenner AJ. Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and MicroRNA expression. J Neurosci. 2011; 31:(9): 3459–3469.

•. Chu Y, Jin X, Parada I, et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci USA. 2010; 107:(17):7975–7980.

•. Stevens B, Allen NJ, Vasquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007; :131:(6):1164–1178.

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