Blood–brain barrier dysfunction may be an early trigger of neurological aging in mice

Written by Sharon Salt, Editor

A recent set of studies have described how blood–brain barrier leakage can affect brain inflammation, leading to accelerated neurological aging in mice. The papers, which have been published in Science Translational Medicine, demonstrated that an experimental model of brain aging, where serum protein albumin was infused into the brains of rodents, could be ameliorated by blocking a signaling pathway in the brain.

The research also revealed that a specific brain wave pattern, sometimes seen in individuals with Alzheimer’s disease, was also observed in rats who had albumin infused into their brains.  

“When we infused albumin into the brains of young mice, we recapitulated aging of the brain: the gene expression, the inflammatory response, resilience to induced seizures and mortality after seizures, performance in a maze,” commented Daniela Kaufer (University of California, Berkeley, CA, USA), senior author of the paper.  

“And when we recorded their brain activity, we found these paroxysmal slow wave events. And all were specific to the site we infused. So, doing this is sufficient to get an aged phenotype of this very young brain,” Kaufer added.  

Subsequently, the researchers genetically engineered the mice so that the TGF-β receptor in astrocytes could be knocked out after they had reached old age. In doing so, the team reported that the “senile” mouse brains were like young mice again. Additionally, the mice were as resistant to induced seizures as young mice and they also learned how to navigate a maze like a young mouse would.  

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Serendipitously, Barry Hart (who is a medicinal chemist) offered to synthesize a small-molecule drug that blocks the TGF-β receptor in astrocytes only and that could traverse the blood–brain barrier. When the drug – termed IPW – was administered to mice in doses that lowered the receptor activity level to that found in young mice, the researchers reported that the brains of the aged mice looked younger.  

The team demonstrated that young brain-like gene expression reduced inflammation and improved rhythms (i.e., reduced paroxysmal slow wave events) as well as reduced seizure susceptibility. They also navigated a maze or learned a spatial task like younger mice.  

From analyzing brain tissue from humans, Kaufer also revealed that there was evidence of albumin in aged brains and increased neuroinflammation and TGF-β production with age. In order to detect leakage in the blood–brain barrier, a special type of MRI imaging – referred to as dynamic contrast-enhanced imaging – was developed, and the researchers noted that more leakage was observed in individuals with greater cognitive dysfunction.  

According to Kaufer, the evidence collectively points towards a dysfunction in the brain’s blood filtration system as one of the earliest triggers of neurological aging.  

“We got to this through this back door; we started with questions about plasticity having to do with the blood–brain barrier, traumatic brain injury and how epilepsy develops. But after we’d learned a lot about the mechanisms, we started thinking that maybe in aging it is the same story. This is new biology, a completely new angle on why neurological function deteriorates as the brain ages,” concluded Kaufer

Cautioning on the findings and their translation to dementia in the press, David Curtis (University College London, UK) stated: “…this study is not really very relevant to the common mechanisms for dementia which we observe in humans. It seems that they have made an intervention which impairs brain function in rodents and then inhibited that mechanism to result in improved functioning. This is very far from being able to, for example, inhibit the mechanisms which underly Alzheimer’s disease or any other specific forms of dementia.”

Sources: Senatorov Jr VV, Friedman AR, Milikovsky DZ et al. Blood–brain barrier dysfunction in aging induces hyperactivation of TGFB signaling and chronic yet reversible neural dysfunction. Sci. Transl. Med. 11(521), eaaw8283 (2019); Milikovsky DZ, Ofer J, Senatorov Jr VV et al. Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood–brain barrier dysfunction. Sci. Transl. Med. 11(521), eaaw8954 (2019); https://news.berkeley.edu/2019/12/04/drugs-that-quell-brain-inflammation-reverse-dementia/www.sciencemediacentre.org/expert-reaction-to-two-papers-on-dementia-looking-at-the-blood-brain-barrier-and-brain-inflammation-in-mice/