Blood-Brain Barrier Dysfunction Causes Chronic Inflammation and Neurodegeneration

Numerous lines of evidence point to the characteristic increase in chronic inflammation that takes place in old age to be of great importance in the progression of neurodegenerative conditions. A fair degree of that inflammation in the brain results from dysfunction of the blood-brain barrier, a layer of cells lining blood vessels in the central nervous system that normally acts to prevent unwanted and potentially harmful molecules and cells from entering the brain. The work reported here builds on more than a decade of investigation of the age-related decline of the blood-brain barrier, and consequent inflammation in the brain, to build a targeted therapy to damp down one very specific source of inflammatory signaling. This is no doubt far from the only mechanism leading to inflammation, and repairing the blood-brain barrier would be a better way forward than compensating for its decline, mechanism by mechanism through a long list of such mechanisms, but the results are nonetheless interesting.

Scientists report that senile mice given an anti-inflammatory drug had fewer signs of brain inflammation and were better able to learn new tasks, becoming almost as adept as mice half their age. "We tend to think about the aged brain in the same way we think about neurodegeneration: Age involves loss of function and dead cells. But our new data tell a different story about why the aged brain is not functioning well: It is because of this "fog" of inflammatory load. But when you remove that inflammatory fog, within days the aged brain acts like a young brain. It is a really, really optimistic finding, in terms of the capacity for plasticity that exists in the brain. We can reverse brain aging."

The successful treatment in mice supports a radical new view of what causes the confusion and dementia that often accompany aging. More and more research shows that, with age, the filtration system that prevents molecules or infectious organisms in the blood from leaking into the brain - the so-called blood-brain barrier - becomes leaky, letting in chemicals that cause inflammation and a cascade of cell death. After age 70, nearly 60% of adults have leaky blood- brain barriers, according to magnetic resonance imaging (MRI) studies.

An accompanying paper shows that the inflammatory fog induced by a leaky blood-brain barrier alters the mouse brain's normal rhythms, causing microseizure-like events - momentary lapses in the normal rhythm within the hippocampus - that could produce some of the symptoms seen in degenerative brain diseases like Alzheimer's disease. Electroencephalograms (EEGs) revealed similar brain wave disruption, or paroxysmal slow wave events, in humans with epilepsy and with cognitive dysfunction, including Alzheimer's and mild cognitive impairment (MCI).

Scientists have long suspected that a leaky blood-brain barrier causes at least some of the tissue damage after brain injury and some of the mental decline that comes with age. But no one knew how. In 2007, researchers linked these problems to a blood protein, albumin. In 2009, they showed that when albumin leaks into the brain after trauma, it binds to the TGF-β receptor in brain cells called astrocytes. This triggers a cascade of inflammatory responses that damage other brain cells and neural circuits, leading to decreased inhibition and increased excitation of neurons and a propensity toward seizures.

In the new studies, researchers showed that introducing albumin into the brain can, within a week, make the brains of young mice look like those of old mice, in terms of hyperexcitability and their susceptibility to seizures. These albumin-treated mice also navigated a maze as poorly as aged mice. When they genetically engineered mice so that they could knock out the TGF-β receptor in astrocytes after they'd reached old age, the senile mouse brains looked young again. The mice were as resistant to induced seizures as a young mouse, and they learned a maze like a young mouse. Researchers developed a small-molecule drug that blocks the TGF-β receptor in astrocytes only, and that could traverse the blood-brain barrier. When they gave the drug, called IPW, to mice in doses that lowered the receptor activity level to that found in young mice, the brains of the aged mice looked younger, too. They showed young brain-like gene expression, reduced inflammation and improved rhythms - that is, reduced paroxysmal slow wave events - as well as reduced seizure susceptibility. They also navigated a maze or learned a spatial task like a young mouse.



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