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Research study shows reduction in seizures and cognitive impairment in aged mice treated with a TGFβ inhibitor

Wednesday 04 December 2019

On 4 December, Vladimir Senatorov, Aaron Friedman and colleagues reported the results of their study on blood-brain barrier breakdown in aging, showing that treatment of aged mice with a TGFβ inhibitor drug can reduce seizures and cognitive impairment.This study, which also evaluated blood-brain barrier breakdown and TGFβ signalling in the brains of aged adults, was published in the Science Translational Medicine journal.

The blood-brain barrier (BBB) is a semi-permeable barrier that separates circulating blood from the brain.  It is composed of specialised vascular cells and the ‘feet’ of astrocytes, which together form a protective sheath around small blood vessels in the brain. In healthy young adults, the BBB effectively filters out blood-borne pathogens and controls the access of different molecules and growth factors to the brain.  However, aging is associated with BBB dysfunction and leakiness, letting in toxic blood-borne molecules and pathogens. Previous studies in aging individuals have shown that BBB breakdown is strongly correlated with cognitive decline and Alzheimer’s disease (AD). Preventing or reducing BBB breakdown could therefore have therapeutic benefits in AD and other aging-associated conditions.  However, there are still gaps in our understanding of the BBB: in particular, we don’t yet know which biological mechanisms cause BBB breakdown in old age.

In this study, Senatorov and Friedman set out to evaluate BBB dysfunction in samples from aged adults and in rodent models of aging. First, they looked at BBB leakiness in aging mice, checking which cell type within the BBB showed signs of dysfunction.  They found that astrocytes within the BBB appeared to be particularly dysfunctional, taking up more and more albumin (a protein that circulates in the blood) as animals aged.  Analysis of these dysfunctional astrocytes revealed enhanced TGFβ signalling, while functional assays showed that BBB breakdown was linked to seizure activity and cognitive impairment in aged mice. 

To check whether this observation in mice could be clinically relevant in humans, the researchers performed MRI scans on 113 individuals aged between 21 and 83 years. Of these 113 individuals, they observed that over 50% showed signs of BBB dysfunction by the age of 60. Importantly, brain gene expression analysis using a publicly-available data resource showed increasing TGFβ expression from 123 individuals as they aged. Finally, the researchers returned to their animal models of aging and BBB breakdown to see whether inhibiting TGFβ signalling could be beneficial. After 7 days of treatment with a drug that inhibits TGFβ signalling, aged mice performed better on cognitive tests and had reduced seizures. 

Taken together, this work indicates that preventing TGFβ signalling in astrocytes can reduce age-related BBB dysfunction in mice.  It also provides tentative clues suggesting that increased TGFβ signalling may be related to BBB leakiness in humans, although it remains to be seen whether TGFβ plays a causative role in this pathological process from a clinical perspective.  Link to article: https://stm.sciencemag.org/content/11/521/eaaw8283

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