Posts Tagged ‘inflammation’

Diagram of the brain of a person with Alzheimer’s Disease.

In recent years, researchers have largely converged on the role of inflammation in the development and progression of Alzheimer’s disease (AD). Studies over the past decade have revealed unexpected interactions between the brain and the immune system, and metabolic conditions such as obesity and diabetes may activate inflammatory responses that contribute to the development and progression of AD.

The activation of the inflammatory response is controlled by the inflammasome, a multi-protein oligomer that promotes the release of several pro-inflammatory cytokines including interleukin 1β (IL-1β) and interleukin 18 (IL-18). In an earlier study, a group of researchers with the University of Massachusetts Medical School, the University of Tokyo and the University of Bonn reported that mice with a cognate of Alzheimer’s disease that were additionally bred to knock out the NLRP3 gene encoding the inflammasome were completely protected from neurodegenerative effects of the disease. The researchers presumed that this was the result of their inability to produce IL-1β and IL-18.

This finding was quite promising, suggesting that targeting components of the inflammasome might be a path to Alzheimer’s treatments. In their new study, they sought to determine the effect of IL-18 by breeding IL-18 knockout mice. The researchers considered IL-18 to be a promising target, because levels are elevated in the cerebrospinal fluid of AD patients with mild cognitive impairment. Additionally, it is known to increase the production of amyloid peptide.

But the result of the new mouse study was startling, and completely unprecedented in Alzheimer’s research. The IL-18 knockout mice developed a lethal seizure disorder that the researchers attribute to an increase in neuronal network transmission. The authors write, “… the effects of IL-18 deletion were so dramatic that we were unable to identify previous evidence to help understand the phenomena.”

The finding that a proinflammatory cytokine might in some way ameliorate seizure-inducing neural activity seems counterintuitive, since inflammation is theorized to promote neurodegenerative symptoms in AD. The researchers believe that epilepsy is understudied in AD patients, even though it is a common complication; they point out that two-thirds of AD patients experience both motor and non-motor seizures. Additionally, AD patients with epilepsy are more likely to develop memory loss and other cognitive symptoms, and experience a more widespread loss of brain cells than AD patients without epilepsy, according to the researchers.

They theorize that IL-18 may be counteracting seizure-promoting effects of IL-1β, and suppressing IL-18 thus induced seizures in the test mice. “In fact,” they write, “the countereffect of IL-18 and IL-1β has been documented in a mouse model of cerebellar ataxia. Importantly, we found that the acute application of IL-18 protein reduced excitatory synaptic transmission in the hippocampus, providing evidence that IL-18 has a protective function in neuronal excitability. Thus, we speculate that IL-18 directly suppresses these proepileptogenic effects of IL-1β in APP/PS1 mice.”

However, the most important implication of the study may be that, while the inflammasome is a promising therapeutic target for Alzheimer’s, inhibiting specific cytokines could negatively affect people with the disease.

More information: Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice. Proceedings of the National Academy of Sciences (2018).

Alzheimer’s disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.
Journal reference: Proceedings of the National Academy of Sciences


By Sarah C. P. Williams

There’s a reason people say “Calm down or you’re going to have a heart attack.” Chronic stress—such as that brought on by job, money, or relationship troubles—is suspected to increase the risk of a heart attack. Now, researchers studying harried medical residents and harassed rodents have offered an explanation for how, at a physiological level, long-term stress can endanger the cardiovascular system. It revolves around immune cells that circulate in the blood, they propose.

The new finding is “surprising,” says physician and atherosclerosis researcher Alan Tall of Columbia University, who was not involved in the new study. “The idea has been out there that chronic psychosocial stress is associated with increased cardiovascular disease in humans, but what’s been lacking is a mechanism,” he notes.

Epidemiological studies have shown that people who face many stressors—from those who survive natural disasters to those who work long hours—are more likely to develop atherosclerosis, the accumulation of fatty plaques inside blood vessels. In addition to fats and cholesterols, the plaques contain monocytes and neutrophils, immune cells that cause inflammation in the walls of blood vessels. And when the plaques break loose from the walls where they’re lodged, they can cause more extreme blockages elsewhere—leading to a stroke or heart attack.

Studying the effect of stressful intensive care unit (ICU) shifts on medical residents, biologist Matthias Nahrendorf of Harvard Medical School in Boston recently found that blood samples taken when the doctors were most stressed out had the highest levels of neutrophils and monocytes. To probe whether these white blood cells, or leukocytes, are the missing link between stress and atherosclerosis, he and his colleagues turned to experiments on mice.

Nahrendorf’s team exposed mice for up to 6 weeks to stressful situations, including tilting their cages, rapidly alternating light with darkness, or regularly switching the mice between isolation and crowded quarters. Compared with control mice, the stressed mice—like stressed doctors—had increased levels of neutrophils and monocytes in their blood.

The researchers then homed in on an explanation for the higher levels of immune cells. They already knew that chronic stress increases blood concentrations of the hormone noradrenaline; noradrenaline, Nahrendorf discovered, binds to a cell surface receptor protein called β3 on stem cells in the bone marrow. In turn, the chemical environment of the bone marrow changes and there’s an increase in the activity of the white blood cells produced by the stem cells.

“It makes sense that stress wakes up these immune cells because an enlarged production of leukocytes prepares you for danger, such as in a fight, where you might be injured,” Nahrendorf says. “But chronic stress is a different story—there’s no wound to heal and no infection.”

In mice living with chronic stress, Nahrendorf’s team reported today in Nature Medicine, atherosclerotic plaques more closely resemble plaques known to be most at risk of rupturing and causing a heart attack or stroke. When the scientists blocked the β3 receptor, though, stressed mice not only had fewer of these dangerous plaques, but also had reduced levels of the active immune cells in their plaques, pinpointing β3 as a key link between stress and atheroscelerosis.

The finding could lead to new drugs to help prevent cardiovascular disease, suggests biologist Lynn Hedrick of the La Jolla Institute for Allergy and Immunology in San Diego, California. “I think this gives us a really direct hint that the β3 receptor is important in regulating the stress-induced response by the bone marrow,” Hedrick says. “If we can develop a drug that targets the receptor, this may be very clinically relevant.”

More immediately, the new observations suggest a way that clinicians could screen patients for their risk of atherosclerosis, heart attack, and stroke, Tall says. “Rather than asking four questions about stress levels, we could use their white blood cell counts to monitor psychosocial stress,” he says.

Thanks to Dr. Rajadhyaksha for bringing this to the attention of the It’s Interesting community.