In the August 21 Science, researchers led by Michal Schwartz and Ido Amit, Weizmann Institute of Science, Rehovot, Israel, report that the choroid plexus, the barrier separating the blood and the cerebrospinal fluid, plays a key role in brain aging. They found that as wild-type mice got older, the balance between immune signals in the tissue shifted. They found similar changes in human postmortem brains. By restoring immune signaling in old animals to that of young whippersnappers, the researchers quelled inflammation and reversed age-related deficits in neurogenesis and memory. “The study opens a new window to the process of brain aging and suggests a completely new age-modulating function for the choroid plexus,” said Costantino Iadecola, Weill Cornell Medical College, New York. “It could be just the tip of the iceberg,” he said, speculating that other points of contact between the blood and brain could contribute a similar function.

Astrocytes (red) flare up in the hippocampus of older mice, but cool off when mice are treated with an antibody that curbs IFN-I responses. (Neuronal nuclei in blue.) [Image courtesy of Science/AAAS.] 

The choroid plexus lines portions of the brain’s ventricles and forms a rare interface between the blood and the cerebrospinal fluid (CSF). It is responsible for producing the latter, pumping out about 500 ml per day. It also supplies nutrients and hormones to the brain while clearing waste. Since the CSF changes with age, Schwartz and colleagues wondered if the choroid plexus might also, and if it could be manipulated to slow age-associated cognitive decline.

To find out, first authors Kuti Baruch and Aleksandra Deczkowska compared mRNA profiles among 11 tissues from 3-month-old and 22-month-old wild-type mice. The choroid plexus alone demonstrated significant changes in interferon signaling. Interferons are cytokines released when a virus invades. Most cell types secrete type I interferons, which make recipient cells resistant to viruses. The type II variety comes from natural killer cells and T lymphocytes and serves as an alert to the immune system. Typical genes that depend on type I interferons include interferon regulatory factor 7, interferon-β 1, and interferon-induced protein with tetratricopeptide repeats 1, according to the Interferome Database hosted by Monash University in Melbourne, Australia. Baruch and colleagues found that transcript levels of all three were higher in aged choroid plexus. At the same time, mRNA typical of an IFN-II response—such as intercellular adhesion molecule 1, interferon γ-induced protein 10, and chemokine (C-C motif) ligand 17, were less abundant. The same signature prevailed in aged wild-type mice from three other institutions. Postmortem brain tissue from healthy older people also demonstrated an uptick in IFN-I-related gene expression.

To figure out whether the signals that brought about these changes came from blood or cerebrospinal fluid, the researchers conducted two sets of experiments. Collaborating with Tony Wyss-Coray at Stanford University, California, they first tested blood by joining the vascular systems of young mice to old via parabiosis (see May 2014 news story). The blood of young mice raised expression of IFN-II related genes in the choroid plexus of older animals. In contrast, the blood of the older mice caused the choroid plexus of the younger mice to express fewer IFN-II-related transcripts. Next, the authors tested the effect of the CSF by bathing primary cultures of young choroid plexus epithelial cells in the fluid. CSF from aged animals caused IFN-I related transcripts to rise. They did not expose epithelial cells from old mice to the CSF of young animals. Together, the parabiosis and cell culture experiments suggest that IFN-II-related signals come from the periphery, while factors inducing the IFN-I genes originate in the brain, Schwartz said.

Could these signals be manipulated to reverse signs of aging? To find out, Baruch and Deczkowska injected antibodies into the CSF to block IFN-I type receptors in old wild-type C57BL/6 mice. They chose mice that fared particularly poorly on object-recognition tasks compared with cognitively intact animals of the same age. The antibodies not only improved memory but reduced inflammation in the brain (see image above) and restored neurogenesis to levels seen in mice that were the same age, yet had preserved cognition. “This study suggests a new approach to treat aging,” said Schwartz. In addition, since IFN-I and IFN-II seem to have a reciprocal relationship, it might be possible to boost IFN-II in the periphery to affect IFN-I signals coming from the brain, she suggested. Schwartz emphasized that this requires further investigation.

Why does older choroid plexus produce inflammatory signals to begin with? Schwartz proposed that when the brain ages, dying cells and inflammatory factors cause a chronic distress signal that continuously elicits an IFN-I response. This could be an important risk factor in age-related neurodegenerative disease, she said. Her lab is now looking in mouse models of Alzheimer’s disease (AD) to determine the influence of type I and type II interferon signals.

Recent studies by Wyss-Coray and others have used parabiosis to seek out as-yet-unknown circulating factors in the blood that hasten or reverse signs of aging in the brain (see Nov 2009 news story). Some propose that the chemokine CCL11 could be one of them, while others contend it is the growth differentiation factor GDF11 (see Aug 2011 news storyMay 2014 conference story on Katsimpardi et al., 2014). “The current study may help explain the age-defying effects of young blood and why aging contributes Alzheimer’s disease," Wyss-Coray told Alzforum. “Cognitive deficits that develop in AD may be influenced by the choroid plexus and through interferon responses,” he added. Age-related changes may also impair the choroid plexus' ability to generate CSF and to produce beneficial factors, he speculated.

Scientists need to next pinpoint the downstream effectors of interferon signaling responsible for these effects, said Iadecola. Richard Ransohoff of Cleveland Clinic added that researchers should seek the upstream factors responsible, too. He was intrigued that these experiments reveal age-related changes in the choroid plexus that are driven by signals from the brain. However, he cautioned that factors other than interferons could drive the gene alterations. “It is premature to tighten the focus to only two cytokines, type I and type II interferons, because other factors can regulate several of these genes,” he told Alzforum. “The most important thing is to gain a deeper understanding for the basis of these gene expression changes, and then focus on their physiologic significance.” He pointed out that improved cognition brought about by the IFN-I receptor antibody indicates a short-term effect of interferon signaling, but says little about long-term, age-related changes in cognition.—Gwyneth Dickey Zakaib

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References

News Citations

  1. In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition
  2. Chicago: The Vampire Principle—Young Blood Rejuvenates Aging Brain?
  3. Paper Alert: Do Blood-Borne Factors Control Brain Aging?

Paper Citations

  1. . Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014 May 9;344(6184):630-4. Epub 2014 May 5 PubMed.

External Citations

  1. Interferome Database

Further Reading

Papers

  1. . CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2264-9. Epub 2013 Jan 18 PubMed.
  2. . Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease. Neurobiol Aging. 2014 May;35(5):1012-23. Epub 2013 Oct 29 PubMed.
  3. . Measurement of choroid plexus perfusion using dynamic susceptibility MR imaging: capillary permeability and age-related changes. Neuroradiology. 2013 Dec;55(12):1447-54. Epub 2013 Oct 23 PubMed.
  4. . Blood--brain-barriers in aging and in Alzheimer's disease. Mol Neurodegener. 2013 Oct 22;8(1):38. PubMed.
  5. . Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev. 2013 Oct;93(4):1847-92. PubMed.

Primary Papers

  1. . Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014 Aug 21; PubMed.