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

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  1. The choroid plexus (CP) is a highly vascularized organ embedded in the cerebrospinal fluid (CSF) of the brain ventricles. The CP epithelium contributes to the production and formation of the CSF and is positioned between the two fluid compartments of the brain, the CSF and blood. In addition to generating CSF, the CP epithelium serves as a principal site of the blood-CSF barrier that contributes to the blood-brain barrier (BBB) system, isolating the brain and CSF from blood-derived factors. The apical side of the CP epithelium faces CSF, whereas the basolateral side faces blood-containing fenestrated type CP capillaries that are different from the BBB capillaries. Multiple degenerative changes in the aging brain have been described in the choroid plexus and ventricular system that could influence normal CSF production, flow and drainage, and the dynamics of brain fluid exchanges. Whether the CP can influence brain functions and neurogenesis in the adult and aging brain, or serves mainly to generate CSF, protect the brain from systemic influences, and help with the CSF “sink” action and clearance functions remains controversial.

    Baruch et al. studied the effects of aging on the CP using multi-organ genome-wide analysis of aged mice. They discovered that the CP, in contrast to other organs, shows a type I interferon (IFN-1)-dependent expression profile that is consistent with their immunostaining results in the aging human brain. IFN-I is normally secreted by lymphocytes, macrophages, endothelial cells, and other cell types, and exhibits anti-viral activity. To isolate blood-derived from brain-derived factors that potentially could be responsible for the observed age-associated increase in the IFN-1-dependent expression profile in the CP, the authors employed the heterochronic parabiosis approach and an in vitro CP epithelial cell culture technique. They showed that circulating factors in young mice did not influence IFN-1 dependent gene expression profile in the CP of older parabionts. This led them to conclude that blood-derived factors did not contribute to the observed senescence-related IFN-1 CP changes. They also showed that the primary cultures of CP epithelial cells, treated with CSF derived from aged mice, displayed an IFN-1-dependent response, leading the authors to conclude that brain-derived signals might have a critical influence on age-associated IFN-1 expression profile in the CP epithelium. Furthermore, they showed that IFN-1 blockade in the CSF of aged mice caused by neutralizing antibodies to IFN-I receptors resulted in improved hippocampus-dependent spatial memory and increased hippocampal neurogenesis and Il-10 expression, the latter known to be associated with the M2-protective microglia phenotype.

    In conclusion, Baruch et al. suggested that the CP may hold a key in normal brain aging and cognitive decline. This is a very intriguing and provocative concept, and more studies should be encouraged to validate the authors’ hypothesis. For example, there is no evidence at present for a role of CP in cognitive decline in humans. This question has not been addressed by Baruch et al., as they did not relate observed CP profile to cognitive status or neuropathological findings. It would be also interesting to know how the reported IFN-1 expression profile relates to CSF findings in individuals with different levels of cognitive impairment. Age-related vascular changes contribute to human dementia in ~40 percent of all cases, including individuals with Alzheimer’s disease. Multiple imaging, functional, and pathological studies have identified that neurovascular dysfunction is associated with cognitive impairment, and some have suggested that may even precede cognitive decline. Whether the CP IFN-1 profile and other degenerative changes are part of an overall degenerative and/or senescent phenotype within the aging brain vascular system and whether age-related changes at the BBB (which has approximately 5,000 times greater surface area that the CP epithelium in the human brain) precede the observed changes in the CP is not known either. Baruch et al. also left open for future studies to find out why the aging CP epithelial cells develop an IFN-1-specific expression profile in a first place. Do changes in the CP precede or follow the observed behavioral changes? Finally, it would be of interest to find out which brain-derived factors lead to a CP aging profile. Are the aging cells within the neurovascular unit that produce brain-derived factors influencing CP IFN-1 profile the primary target for the development of therapeutics, or the CP epithelium? More work should be stimulated by this interesting and important study. 

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  1. Choroid Plexus May Hold a Key To Aging Brain