Nicotine, the active agent in tobacco, and amyloid proteins, which underlie Alzheimer’s disease, bind to a receptor present in certain immune cells and work to lessen inflammation, a study reports. Activating this receptor — called the α7 nicotinic acetylcholine receptor — was seen to ease multiple sclerosis (MS) progression in a mouse model of the disease.
These results support the development of small-molecule therapies targeting this receptor to possibly treat MS and other inflammatory diseases.
The study, “Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine” was published in the journal PNAS.
Researchers at Stanford University School of Medicine, in a study reported in 2012, found that beta-amyloid — the small peptide whose build-up in the brain is the cause of Alzheimer’s disease — had a therapeutic effect in a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE) model.
They showed that both beta-amyloid and its precursor protein, the amyloid precursor protein, are found in MS lesions. Their presence, along with damage to the protective myelin coating on nerve cell’s axons, are hallmarks of MS.
Axons are the long, slender nerve cell projections whose job is to transmit information (electrical impulses) to other neurons, muscles, and glands. In MS, immune cells invade the brain and spinal cord, and attack myelin.
Researchers reported in the earlier study that injecting beta-amyloid into EAE mice prevented or delayed the onset of paralysis, an outcome of the immune attacks and myelin loss seen in MS. The therapeutic effect of beta-amyloid injections were seen irrespective of the timing, i.e., before or after the mice developed symptoms of paralysis.
Further experiments also showed that beta-amyloid’s therapeutic effects had nothing to do with its effects on the brain, but rather it acted on immune cells directly and before they penetrate the central nervous system.
The beneficial role of beta-amyloid in MS was further supported in an experiment with mice who had been engineered to lack amyloid-beta or its precursor protein completely. After infusing these mice with immune cells prone to attack myelin, triggering an MS-like state, the animals not only more severe MS-like symptoms but succumbed to the disease more quickly and more frequently than control mice who were also given these myelin-targeting immune cells.
A follow-up study reported in 2013 that small portions of several amyloid-forming proteins, like tau and prion proteins — all relevant as drivers of Alzheimer’s disease — could quickly alleviate MS symptoms in mouse models.
But how and why these amyloid-forming proteins are protective in MS remained unanswered — a question the current study addressed, the researchers said in a university news story by Bruce Goldman.
They found that the amyloid-forming proteins bind and activate the α7 nicotinic acetylcholine receptor (α7 NAChR) present in certain cells of the immune system — namely, in macrophages in the abdomen cavity and subtypes of antibody-producing cells called B-cells.
Binding amyloid-forming proteins to the α7 NAChR triggered an immune response shutdown. This receptor is also the target of nicotine, tobacco’s pharmacologically active ingredient, which has also been shown to be an effective therapeutic in the EAE mouse model.
Treatments in the form of small compounds that activate the immune suppressive functions of the α7 NAChR may benefit MS patients, and potentially those with other immune-related disorders, such as rheumatoid arthritis and inflammatory bowel disease, the researchers said, adding they are working to develop therapies targeting the α7 NAChR receptor.
“The data further support the realization that amyloid fibrils are immune suppressive, which may be an important factor in neurodegenerative diseases,” their study concludes. “The demonstration that NAChR agonists are effective in limiting … autoimmunity emphasizes that the α7-specific partial agonists, which failed in clinical trials for Alzheimer’s disease and schizophrenia, could be reconsidered as therapeutics for a spectrum of inflammatory indications.”
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