Mayo Clinic LogoIn an astonishing reversal of long-standing scientific belief, researchers at the Mayo Clinic campus in Florida have revealed that inflammation in the brain may not be the trigger that leads to increase of amyloid deposits and development of Alzheimer’s disease.

The researchers claimed that actually, inflammation assists in clearing the brain of these noxious amyloid plaques early in the disease development, as observed from studies in mice that are prone to the disorder.

“This is the opposite of what most people who study Alzheimer’s disease, including our research group, believed. And it also suggests that we can take advantage of the brain’s own immune cells by directing them to remove amyloid plaques from the brain, thus protecting the brain against their harmful effects,” says lead investigator, Pritam Das, Ph.D., an assistant professor in the Department of Neuroscience.

This research was believed to have tested the commonly held belief that inflammation in the brain seems to augment the production and buildup of a toxic protein known as amyloid beta (Aβ). Bunches of this protein inside the brain are known to be the characteristic pathological feature of Alzheimer’s disease.

Dr. Das further stated that, “The belief was that when the brain’s immune cells, microglia, are activated following the initial buildup of amyloid plaques, the inflammation that ensues stimulates the brain cell’s machinery to produce more Aβ, which then leads to more inflammation.”

“This chronic activation of immune cells results in a self-reinforcing feedback loop that promotes more and more Aβ deposition and inflammation, eventually leading to malfunction and death of brain neurons,” continues Dr. Das.

Even though this notion, which came mostly from researches in laboratory cells, was accepted all over the scientific community, the Mayo Clinic researchers were believed to have developed a method in order to test it in a living organism where they anticipated in seeing a similar result.

“We had initiated these studies using our new in vivo model to confirm whether inducing inflammation in the brain would in fact exacerbate the disease,” adds Dr. Das.

In order to increase expression of Interleukin-6 (IL-6), the researchers were noted to have made use of a technique known as ‘Somatic Brain Transgenesis’. IL-6 is known to be a cytokine that stimulates an inflammatory immune response inside the brains of young mice prone to develop age-progressive amyloid plaques.

This powerful technology seems to allow researchers to express any gene of interest in definite parts of the body by tagging the gene onto Adeno-associated viruses which are inert. In this way, they could possibly examine the function of any protein in the brain, and also test its possible therapeutic use.

They discovered that IL-6 seems to have triggered inflammation all through the brain. In addition, they expected to see a big increase of plaque as well as damage to brain neurons.

“Instead, to our surprise, we found that the inflammation prevented plaques from forming and cleared whatever plaque that was already there,” says Dr. Das.

Given this unexpected result, the researchers were noted to have performed further experiments using different strategies.

Dr. Das further said that, “First, we expressed IL-6 in the brains of newly born mice that are yet to develop any amyloid plaques and, secondly, we expressed IL-6 in the brains of mice with pre-existing plaque pathology. In both these cases, we got similar results — the presence of IL-6 leads to the clearance of amyloid plaques from the brain.”

The researchers were then believed to have performed experiments in order to determine how the amyloid plaques were removed from the brain. Their investigation revealed that the inflammation induced by IL-6 in the brain seems to have directed the microglia cells to remove the amyloid plaques from the brain. Supposedly, microglial cells do this through phagocytosis.

“They gobble up the plaque, which they ‘see’ as a foreign invader, and break it apart,” says Dr. Das.

Researchers also found that activated microglia cells appear to be strongly attached to the plaques and expressed proteins that assist in removing the amyloid plaques from the brain.

“Indeed, it may be feasible to transiently and selectively manipulate the microglia cells to alter amyloid plaques in a manner that is both effective and tolerable. However, given that chronic inflammation over years of insult may be detrimental, any intervention based on activation of the brain’s immune system must clearly strike a balance between the neuroprotective and neurotoxic effects,” Dr. Das cautions.

He puts forward that inflammation may perhaps help clear plaque early in the development of Alzheimer’s disease. However, at some point, continued production of the amyloid clumps in the brain seems to overcome the ability of microglial cells to perform their function. Just then, inflammation, chronically activated by presence of the amyloid plaque, could possibly generate its own unhealthy effects on brain function.

Dr. Das was of the opinion that they require to investigate this phenomenon more comprehensively. However, if they are right, it could possibly have implications not only for Alzheimer’s disease but also for other neurodegenerative disorders characterized by protein buildup in the brain, such as Parkinson’s disease.

The findings of the research have been published in the online issue of the Federation of American Societies for Experimental Biology (FASEB) Journal.