Drugs that tamp down inflammation in the brain could reverse the cognitive decline

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In a publication appearing today in the journal Science Translational Medicine, University of California, Berkeley, and Ben-Gurion University scientists report that senile mice given one such 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,” said Daniela Kaufer, a UC Berkeley professor of integrative biology and a senior author, along with Alon Friedman of Ben-Gurion University of the Negev in Israel and Dalhousie University in Canada.

“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 Friedman’s magnetic resonance imaging (MRI) studies.

An accompanying paper by the two researchers and Dan Milikovsky of Ben-Gurion University 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).

Together, the papers give doctors two biomarkers — leaky barriers detectable by MRI and abnormal brain rhythms detectable by EEG — that can be used to flag people with blood-brain barrier problems, as well as a potential drug to slow or reverse the consequences.

“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,” said Kaufer, a member of UC Berkeley’s Helen Wills Neuroscience Institute.

“You can follow them, and when the blood-brain barrier is healed, you no longer need the drug.”

Blood-brain barrier

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, however, Friedman and Kaufer 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 (TGF-beta) 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.

They also showed in mice that blocking the receptor with an antihypertension drug, losartan, prevented the development of epilepsy after brain trauma.

Epilepsy is a frequent consequence of concussions like those sustained by soldiers from roadside bombs.

Subsequent studies revealed leakiness in the barrier after stroke, traumatic brain injury and football concussions, solidly linking albumin and an overexcited TGF-β receptor to the damage resulting from these traumas.

In their new studies, Kaufer and Friedman 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 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. And when we recorded their brain activity, we found these paroxysmal slow wave events,” Kaufer said.

“And all were specific to the site we infused. So, doing this is sufficient to get an aged phenotype of this very young brain.”

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.

Serendipitously, a Palo Alto, California, medicinal chemist, Barry Hart, 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 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.

This shows brain scans from the study

Dynamic contrast-enhanced MRI (DCE-MRI) scans show that with age, the blood-brain barrier becomes leakier. This dysfunction in shown in both humans and mice.

A leaky BBB triggers a cascade of cell death that may be the cause of age-related cognitive decline. The image is credited to Alon Friedman and Daniela Kaufer.

In analyzing brain tissue from humans, Kaufer found evidence of albumin in aged brains and increased neuroinflammation and TGF-β production with age.

Friedman developed a special type of MRI imaging — dynamic contrast-enhanced (DCE) imaging — to detect leakage in the blood-brain barrier and found more leakage in people with greater cognitive dysfunction.

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

Kaufer, Friedman and Hart have started a company to develop a drug to heal the blood-brain barrier for clinical treatment and hope that the drug will help reduce brain inflammation — and, thus, permanent damage — after stroke, concussion or traumatic brain injury, and eventually help older adults with dementia or Alzheimer’s disease who have demonstrated leakage of the blood-brain barrier.

“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,” Kaufer said. “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.”

Funding: This work was supported by the National Institutes of Health (R01NS066005, R56NS066005), European Union’s Seventh Framework Program, Israel Science Foundation and United States-Israel Binational Science Foundation.


Alzheimer’s disease (AD) is the most common cause of dementia, with no existing treatment that can significantly delay or reverse AD-associated cognitive decline or pathological changes.

The gross histopathology of AD is characterized by brain atrophy, deepening of the cerebral grooves and the enlargement of the cerebral ventricles.

Histologically, AD is characterized by extracellular deposition of amyloid-β (Aβ), intracellular accumulation of neurofibrillary tangles (NFTs) (Alzheimer et al., 1995), and chronic inflammation (McGeer et al., 19871988Griffin et al., 1989Cacabelos et al., 1994).

Aβ has been considered as a main culprit of AD, and the Aβ hypothesis has been dominant for explaining the pathogenesis of AD (Hardy, 2009).

There is a plethora of evidence that support the Aβ hypothesis: patients with an extra copy of chromosome 21, where the APP gene locates, develop dementia at an early age; APP transgenic mice exhibit significant cognitive impairment; the toxicity of Aβ has been documented extensively in in vitro studies (Del Bo et al., 1995Combs et al., 2001Wicklund et al., 2010).

Results from genetic studies have shown an association of inflammation-related genes with AD (Griciuc et al., 2013).

Further, microglia activation as well as elevated pro-inflammatory mediators observed in postmortem AD brains and in AD mice models support that chronic inflammation is an integral part of AD pathogenesis (Heppner et al., 2015).

Inflammation resolution is an active regulatory process in the end stage of inflammatory reaction that can terminate inflammation and initiate repair of damaged tissues rather than passive disappearance of inflammatory mediators as previously believed (Serhan, 2017). Inflammation resolution is mediated by a group of lipid mediators called specialized pro-resolving lipid mediators (SPMs) including lipoxins (LXs), resolvins (Rvs), protectins (NPDs), and maresins (MaRs), all of which are biosynthesized from polyunsaturated fatty acids (PUFAs) via cyclooxygenases (COXs) and lipoxygenases (LOXs) (Serhan, 2014).

In humans, studies have found that reduced SPMs lead to failure of inflammation resolution that can contribute to chronic inflammation diseases such as atherosclerosis (Fredman et al., 2016), dry eye pathogenesis (Gao et al., 2015) as well as AD (Wang et al., 2015).

Evidences from recent studies demonstrate that inflammation resolution is impaired in AD and stimulation of inflammation resolution showed beneficial effects in AD related in vivo and in vitro models (Wang et al., 2015Zhu et al., 2016).

The conversion from dietary FAs to ω-3 FAs, which are precursors of SPMs has been reported to be decreased in the liver of AD patients (Kang and Rivest, 2012). Accordingly, we have previously found that the levels of SPMs were lower in different areas of the postmortem AD brains including the hippocampus and the entorhinal cortex (Lukiw et al., 2005Wang et al., 2015).

Interestingly, results from clinical trials using PUFAs to treat AD patients showed that ω-3 FAs treatment has beneficial effects only on the patients with mild cognitive impairment (MCI) (Yurko-Mauro et al., 2010) but not on late stage AD patients.

Therefore, it is plausible that SPMs are the effective factors mediating the protective effects of ω-3 FAs, however, the conversion from FAs to SPMs is decreased in late stage AD patients. Hence, we hypothesized that SPMs treatment is more effective for AD patients.

Afterward, we tested this hypothesis on AD related cellular models including neuronal and microglia models and observed that all the types of SPMs could improve neuronal survival, and MaR1 was more effective in microglial phagocytosis of amyloid-β(Aβ)42 (Zhu et al., 2016), indicating that inducing inflammation resolution by SPMs especially by MaR1 could be a novel therapeutic strategy for AD. MaR1 synthesis is initiated by the 14-lipoxygenation of DHA to yield 14S-hydro(peroxy)-4Z,7Z,10Z,12E,14S,16Z,19Z-docosahexaenoic acid and then to 13S, 14S-e MaR. This intermediate is then enzymatically hydrolyzed to MaR1 (Deng et al., 2014Dalli et al., 2016).

The biological functions of MaR1 have been showed in various disease models: MaR1 has to stimulate the pro-inflammatory M1 to anti-inflammatory M2 macrophage phenotype shifts and tissue regenerative actions of MaR1 have also been reported (Dalli et al., 2013). Moreover, MaR1 has been reported suppressed oxidative stress in a left pulmonary hilum I/R mouse model (Sun et al., 2017).

However, the effects of MaR1 on AD animal models have not been studied, and the mechanisms underlying the protective effects of MaR1 remain less understood. The aim of this study was to investigate the effects of MaR1 on behavioral deficits and pathological changes induced by intra-hippocampal injection of Aβ42 protein in a mouse model along with the molecular mechanisms of action of MaR1.


Source:
UC Berkeley
Media Contacts:
Robert Sanders – UC Berkeley
Image Source:
The image is credited to Alon Friedman and Daniela Kaufer.

Original Research: Closed access
“Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction”. Alon Friedman et al.
Science Translational Medicine doi:10.1126/scitranslmed.aaw8954.

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