Support the 1st Web Resource in Neuroendocrine-Immunology & Stress-Immune Interactions

Hyperactive Type I Interferon System in the Choroid Plexus Linked To Aging and Cognitive Dysfunction

Hyperactive type I Interferon System Choroid Plexus Aging
Hyperactive Interferon System – Choroid Plexus – Aging

Update at BrainImmuneA study published in the August 21, 2014 issue of Science magazine demonstrates that aging is associated with an overactive interferon (IFN)-I system at a specific brain structure, the choroid plexus.

This vascular tissue, found in all cerebral ventricles, is an epithelial monolayer that forms the blood-cerebrospinal fluid barrier, and, in fact, represents the ‘interface’ between the brain and the circulation.

Interferons are large group of proteins, discovered in 1957, and mostly involved in the protection against viral infections.

Previous research indicates a link between the overproduction of type I interferons (IFN-I) in the central nervous system (CNS) and memory impairments in several neuro-inflammatory human diseases. In addition, neurological and neuropsychiatric complications are often reported in patients with hepatitis C and cancer, treated with IFN-α.

In the Science study, Kuti Baruch and colleagues from the Weizmann Institute of Science, Rehovot, Israel found that brain sections of mice or postmortem brain sections from non-CNS-diseased humans had aging-associated over-expression of IFN-I at the choroid plexus, and this was driven by signals from the brain, present in the cerebrospinal fluid.

Of note, the authors also showed that treatment of epithelial cells from the choroid plexus with IFN-β (key member of the IFN-I family of cytokines) suppressed the expression of insulin-like growth factor (igf1) and brain derived neurotrophic factor (bdnf), molecules that are essential for neuronal growth and survival.

Importantly, administration of neutralizing antibodies to the IFN-I receptor (α-IFNAR), counter-acted IFN-I signaling within the brain which allowed cognitive function to be restored in aged mice. Noteworthy, this was accompanied by an enhanced hippocampal neurogenesis and expression of the anti-inflammatory cytokine interleukin-10, and a decrease in astrogliosis and microgliosis.

Thus, besides the new important research insights, the study suggests that neutralizing type I IFNs response within the CNS may provide new therapeutic target or approach to control or prevent age-associated cognitive decline.

Source: Science DOI: 10.1126/science.1252945, Published Online August 21 2014
Read More: Science
alzforum.org

Updates

A 2015 study used the J20 mouse model of Alzheimer’s disease (AD) and investigated the changes in the choroid plexus transcriptome at the ages of 3, 5–6 and 11–12 months, in comparison with age-matched WT mice.

The most important observation was that the choroid plexus of J20 mice displayed an overall overexpression of type I IFN response genes at all ages. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3 months.

A 2022 study depicts type I IFN as a major driver of memory and cognitive loss in a mouse model of Alzheimer’s disease.

Using a fate-mapping reporter system to track cellular responses to IFN-I, the authors detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types. Moreover, they show that IFN-I-activated microglia and other brain cells arise and expand with amyloidosis; pre and post-synaptic loss are IFN-I dependent and mediated by different cell types, and that IFN-I signaling in neural cells promotes plaque accumulation.

As per News Medical Wei Cao, the last author of this study stated that “the current understanding is that, in addition to having β-amyloid plaques and tau protein tangles, the brains of patients with Alzheimer’s disease have a marked inflammatory response”. And “we found that the IFN-mediated inflammation pathway is rather harmful to the synapses, affecting memory and cognitive performance, and that, importantly, blocking the pathway restores these cognitive abilities,” Cao said.


Cover Image, right panel. CSF circulation, by Mark D. Shen – Shen MD. Cerebrospinal fluid and the early brain development of autism. J Neurodev Disord. 2018;10(1):39. Published 2018 Dec 13. https://dx.doi.org/10.1186%2Fs11689-018-9256-7, via Wikipedia, Public Domain. Schematic of CSF circulation, CSF outflow systems, and the anatomy of various CSF compartments. CSF is produced by the choroid plexus in the ventricles, where it delivers growth factors to progenitor cells that originate on the surface of the ventricles, and then proliferate into neurons and migrate to form the cerebral cortex. CSF circulates from the lateral, third and fourth ventricles to the cisterns of the brain, and then flows into the subarachnoid space, where it envelops the cortical convexities of the brain (EA-CSF). Inset box: From the subarachnoid space, there is retrograde influx of CSF into the parenchyma, where CSF and interstitial fluid interact in the perivascular space, alongside blood vessels that course throughout the brain. Astrocytes lining the perivascular space aid in transporting fluid that removes inflammatory waste proteins (e.g., Aβ), which are continually secreted by neurons as byproducts of neuronal activity and would otherwise build up in the brain. Finally, fluid carrying these inflammatory waste products returns to the subarachnoid space (EA-CSF) and drains into meningeal lymphatic vessels and arachnoid granulations.

Related stories you may like:
Meningeal Interferon-γ Affecting Neuronal Connectivity and Social Behavior
Interferon and the Central Nervous System
Interferon-γ Levels and Chronic Fatigue Syndrome
Anxiety Linked to High IFN-γ and TNF-α