Aging-induced type I interferon response at the choroid plexus negatively affects brain function

Abstract

Age-associated cognitive decline is affected by factors produced inside and outside the brain. We found in aged mice and humans, that the choroid plexus (CP), an epithelial interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent expression profile, often associated with anti-viral responses. This signature was induced by brain-derived signals present in the cerebrospinal fluid of aged mice. Blocking IFN-I signaling within the brain of cognitively-impaired aged mice, using IFN-I receptor neutralizing antibody, led to partial restoration of cognitive function and hippocampal neurogenesis, and reestablished IFN-II-dependent CP activity, lost in aging. Our data identify an aging-induced IFN-I signature at the CP, and demonstrate its negative influence on brain function, thereby suggesting a potential target for therapeutic intervention for age-related cognitive decline.

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

“…Recent evidence has implicated the choroid plexus as a gateway for immune signals reaching the brain (53,54), and in support of this hypothesis, high levels of IgG were present within the choroid plexus of immune-intact mice. Emerging evidence implicates choroid plexus dysfunction in AD (55,56). Thus, it is possible that the choroid plexus regulates the influx of IgG into the brain.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Epithelial cells also express a large repertoire of receptors for diverse molecules, including neurotransmitters, hormones, cytokines, growth factors, and bacterial toxins. As such, they can sense signals in both the CSF and blood, both of which can differentially affect the transcriptome and secretome of choroid plexus epithelial cells [9]. How other choroid plexus cell types respond to external inputs from the circulatory, autonomic, and immune systems and in turn change their secretome is still unknown.…”

“…The CSF composition exhibits circadian and seasonal fluctuations, which are at least in part due to dynamic changes in the choroid plexus [112,138]. As outlined above, the choroid plexuses can modulate physiologiocal states, such as aging [9,137]. The choroid plexuses are also targets for sex hormones, and can, therefore, elicit gender-specific effects [124] with important implications for physiology.…”

“…During aging, a Type I interferon transcriptional program is increased specifically in the LVCP, due to CSF-derived signals but not factors in the circulation [9]. Blocking Type I interferon signaling in the CSF of aged mice partially rescued cognitive defects and hippocampal neurogenesis, and re-activated Type II interferon choroid plexus activity, which is high in young adults, but lost in aging [9]. The LVCP, therefore, is an important regulator of both adult neural stem cell niches.…”

“…With its position at the interface between the blood and the CSF, the choroid plexuses are uniquely placed to sense physiological states and integrate local and long-range signals from the circulation, nervous system, and immune system [9,88] (Fig. 5c).…”