Two compelling new studies are building on a hypothesis suggesting age-related dementia is caused by a leaky blood-brain barrier, triggering neuro-inflammation and, ultimately, brain cell damage. The research reveals a novel anti-inflammatory drug can reverse brain aging in senile mice, but experts suggest the studies are interesting but not particularly applicable to human cases of dementia.
“We tend to think about the aged brain in the same way we think about neurodegeneration: Age involves loss of function and dead cells,” says Daniela Kaufer, UC Berkeley professor and senior author on one of the new studies. “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.”
Scientists are increasingly looking at inflammation as a potential cause for the cognitive deficits seen in everything from normal aging, to Alzheimer’s and other neurodegenerative diseases. Just recently a handful of new studies explored the links between inflammation and acute cognitive impairment, however, the causal mechanisms behind such associations are still unclear.
Kaufer and her colleagues have, for several years, been studying how epilepsy develops following traumatic brain injury. They previously discovered that episodes, such as stroke or football concussions, can damage the all-important blood-brain barrier, our body’s shield protecting the brain from the many infectious agents and damaging molecules traveling through our bloodstream.
The past research discovered a leaky blood-brain barrier allows a protein called albumin to sneak into the brain, triggering a chain of inflammatory actions ultimately resulting in epileptic seizures. As the years passed and the team’s research progressed, a novel hypothesis was raised. What if this neurological mechanism they had discovered also underpinned the neurological declines seen in 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,” says Kaufer. “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.”
It wasn’t such a crazy proposal. Several Alzheimer’s researchers over the past few years have raised strong hypotheses associating the neurodegenerative disease with a breakdown of the blood-brain barrier. One study even confidently suggested blood-brain barrier leakage may be one of the earliest pathological signs of Alzheimer’s, signaling the presence of the disease years before other physiological or cognitive impairments surface.
To better understand whether this leaky blood-brain barrier mechanism could be playing a role in fundamental brain aging, the researchers conducted a number of new animal experiments. They first tested whether administering albumin into the brains of young mice would dramatically affect their behavior.
“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,” explains Kaufer. “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.”
The next question was whether pharmacologically disrupting the inflammatory cascade in the brain triggered by albumin could slow, or even reverse, the pathological and behavioral signs of brain aging.
When albumin enters the brain it seems to over-excite TGF-beta receptors in brain cells called astrocytes. It is this increased neuronal excitation that the researchers first linked to epileptic seizures, and later to general brain aging. A new drug was subsequently developed that could cross the blood-brain barrier and specifically block TGF-beta activity in astrocytes only.
The novel drug delivered impressive results in the mouse studies, essentially making the old mouse brains look young again. Brainwave rhythms, gene expression, and general inflammation in the old mouse brains all shifted to resemble their young counterparts after the TGF-beta blocking drug was administered. And, the old mice delivered results on several cognitive tests equal to the younger mice.
Finally, the researchers examined several brain tissue samples from aging human subjects and confirmed age-related increases in the volume of albumin, TGF-beta and neuroinflammation. This suggests the mechanism identified in the animal models could translate to human brains.
So what does all this research mean? Unfortunately, not much more than an academic insight into rodent brain aging, according to several experts in the field.
“Experiments in mice may not translate to humans; put another way just because a drug works in mice it doesn’t mean that it will work in humans,” says Ian Maidment from Aston University. “Over the last few years, many drugs for dementia that showed promise in animal studies failed to work in clinical trials in humans.”
Alongside this important point, David Curtis from University College London suggests the new research zooms in on specific age-related mechanisms in animals that do not particularly correlate with human neurodegenerative diseases such as dementia or Alzheimer’s.
“So far as I can see this study is not really very relevant to the common mechanisms for dementia which we observe in humans,” says Curtis. “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.”
The key question hanging over this research is a pretty simple one. How transferable are these findings to human dementia? And considering how many Alzheimer’s drug therapies have failed in recent years, it is fair to question the transferability of animal results on this topic.
Perhaps the most tangible outcomes from this research are the new ways doctors can test patients for blood-brain barrier problems. Two novel tests were developed in the course of the work that the scientists suggest can be used to identify the state of a patient’s blood-brain barrier. Using EEGs to detect abnormal brain rhythms and a new MRI technique called dynamic contrast-enhanced (DCE) imaging, clinicians can now better identify patients with leaky blood-brain barriers.
Kaufer and several of her colleagues have started a new company that will work to develop a safe and effective drug that can repair the blood-brain barrier. The idea is that stopping this blood-brain leakage will reduce neuroinflammation and potentially help a variety of different patients, from older adults with dementia to younger adults looking to avoid permanent neurological damage after concussion or traumatic brain injury.
“We now have two biomarkers that tell you exactly where the blood-brain barrier is leaking, so you can select patients for treatment and make decisions about how long you give the drug,” says Kaufer. “You can follow them, and when the blood-brain barrier is healed, you no longer need the drug.”
The two new studies were published in the journal Science Translational Medicine.
Source: UC Berkeley
Is it acceptable some type of antibiotic therapy, as it was done in the finally unexistent 'Chronic borreliosis'?
I'd say dangers are small in a pair of 4 weeks courses of a wide spectrum beta-lactamic, let's say Amoxy-Clavulanic, then, or before, tbd, a macrolide, and finally some antiherpes. Addressing CMV, proposed as causative factor in Glioblastoma, has a too high drug cost.