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September 2003

Inflammation and the aging brain
By Dale Kiefer

Inflammation is now thought to play a role in pathological conditions ranging from anemia and allergy to coronary heart disease, psoriasis and even stroke. From inflamed gums that may contribute to cardiovascular disease, to playing a crucial role in fanning the flames of cancer cell growth, inflammation has been implicated in many more diseases than was previously believed.

Recently, inflammation has also been recognized as playing a central role in the debilitating cognitive decline that characterizes neurological disorders such as Alzheimer’s disease and vascular dementia. Although mental decline and memory loss have long been considered inevitable hallmarks of old age, new research suggests that such inflammation/age-associated decline is avoidable. Indeed, findings reported by some scientists suggest that early intervention in low-grade inflammation may offer some protection against these dreaded brain diseases.  

The many guises of inflammation
Inflammation is as familiar as an overworked muscle, and as common as your latest sunburn. Parents who have agonized over a child’s escalating fever know that inflammation occasionally transcends the merely annoying to become something far more troubling: Fever that climbs too high for too long can inflict serious, even life-threatening, damage.

But inflammation, including fever, serves a useful purpose in the body. Even sunburn is a result of the body’s attempt to repair damage inflicted by ultraviolet radiation. In fact, inflammation is an ingenious adaptation that allows the body to defend against clear and present dangers.

For instance, when virulent bacteria invade, they thrive precisely at the body’s normal temperature of 98.6 ºF (37 ºC). Once established, they pour toxins into the bloodstream, while continuing to proliferate exponentially. The immune system mounts a defense, but cellular defenders may be thwarted or simply overwhelmed. In response, the body turns up the furnace. Sensitive to the slightest temperature increases, pathogens perish. The body wins the battle. Fever breaks and all is well.

This is just one example of inflammation’s beneficial nature. But some inflammation goes too far. Fever doesn’t always vanquish the invading horde and fade back to a state of disease-free normalcy. Occasionally the cost of battle is too dear and fever damages the very body it is defending. Autoimmune diseases provide another example of inflammation gone awry. The immune system targets the body’s own tissues by its inability to differentiate between some of the body’s proteins and foreign invaders. In essence, the immune system wages war, against itself. Diseases such as rheumatoid arthritis and lupus erythematosus are the result. Clearly, inflammation can be a double-edged sword.

News from the hot zone
The inflammation of most concern, however, generally goes unnoticed. It is this low-grade chronic inflammation (as opposed to the acute, intense inflammation associated with a healing wound, for instance) that is believed to underlie the most serious neurodegenerative diseases. Huntington’s disease, for example, is characterized by chronic brain inflammation caused by the immune system’s misguided attempts to eliminate a defective protein that results from a genetic defect. And although their inflammation triggers are different, diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (Lou Gehrig’s disease, or ALS) and even multiple sclerosis, are also characterized by chronic inflammation of neural tissues.

Regarding Alzheimer’s disease, one research team noted, “Inflammation is becoming increasingly substantiated as a contributor to Alzheimer’s disease pathogenesis”1 For this reason anti-inflammatory drugs, such as the non-steroidal anti-inflammatory drugs (NSAIDs, e.g. aspirin, ibuprofen and acetaminophen) and the newer COX-2-inhibitor class of prescription drugs, are under investigation as therapies for this and other inflammation-related diseases.

Inflammation and the brain
To better understand inflammation’s role in disease, it’s helpful to comprehend its more benevolent role in keeping the body healthy. Inflammation is the body’s response to a perceived threat. In the case of an invasion by bacteria, the immune system correctly identifies the unwelcome entity and attempts to neutralize it. This involves a complex chain of events and may require the cooperation of a variety of specialized cells. Their activity is generally beneficial, but the goal is always the same: to rid the body of intruders and to dispose of damaged tissue so healing may take place.

Throughout most of the body, cells known as macrophages act as living soldiers, searching for invaders, and then engulfing and neutralizing them. In the brain, supporting cells of the glial family, known as microglial cells, act as scavengers, in much the same fashion as macrophages. They engulf and eliminate dead neurons that have been damaged by injury or illness. Unfortunately, they also secrete harmful neurotoxins and toxic oxygen free radicals in an attempt to neutralize foreign or undesirable substances.2

Regrettably, the inflammatory response is occasionally worse than the stimulus that triggered it in thefirst place. Even when the original trigger is eliminated, inflammation may become self-perpetuating. Such, apparently, is the case in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, ALS and multiple sclerosis, which are characterized by a great deal of microglial activity. The presence of activated microglial cells is an indicator of chronic inflammation.3,4

Alzheimer’s and inflammation
Much remains to be elucidated regarding the onset and progression of Alzheimer’s disease, but it seems clear that an inflammation-provoking protein fragment, a peptide known as amyloid-B, triggers inflammation. Uninterrupted, the inflammation gradually accelerates, killing nerve cells and causing a drastic decline in levels of a vital brain chemical, the neurotransmitter acetylcholine. This downward spiral of neural degeneration commences with the induction of nearly undetectable inflammation, progresses to the erosion of memory, concentration and learning ability and ends with death. Upon demise, Alzheimer’s patients display abnormal spaghetti-like neuritic amyloid-B plaques and neurofibrillary tangles. Like a battleground littered with the remains of the combatants, these damaging plaques are associated with reactive microglial cells, and consist of amyloid-B protein fragments, immune system proteins such as interleukin-6 (IL-6)and other components indicating long-term, and ultimately counterproductive, inflammation.5