By David N. Leff

Science Editor

A violent blow to the head can increase its victim's chances of getting Alzheimer's disease.

If the cranial injury is severe enough to cause loss of consciousness, balance or vision, such a brain concussion may set in motion a train of events leading to cerebral inflammation.

A major molecular player in this inflammatory scenario is a big, bulky protein called amyloid precursor protein (APP). Its major claim to fame is as a progenitor of senile amyloid plaques, a hallmark (but not necessarily the cause) of Alzheimer's disease (AD).

That traumatic insult to the brain also galvanizes the organ's microglial cells, which take countermeasures to contain the initial damage.

Another marker molecule in AD is an apolipoprotein, APO-E, better known as an escort of cholesterol—itself infamous as a forerunner, in the blood, of atherosclerosis.

A research paper in today's Nature, dated Aug. 28, 1997, reports new findings on how these disparate molecular elements act in concert to prevent or to provoke Alzheimer's disease. It bears the title: "Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E."

The article's principal author is cellular neurobiologist Steven Barger, at the University of Arkansas for Medical Sciences, Little Rock. "Our most basic findings," he told BioWorld Today, "are that APP can induce some signs of inflammation in the relevant cells from brain tissue, and that this activity can be modulated by APO-E in a way that's specific to APO-E3 or APO-E4." (See BioWorld Today, July 16, 1996, p. 1.)

Barger explained: "We think that APO-E3 is binding fairly near the center of the APP molecule, and modulates activities in those regions." He added, "It looks as if APO-E4 sticks with lower affinity, so it will be less efficient at affecting APP's functions."

Those functions are dual in nature: beneficial or detrimental, Barger pointed out. "APP can protect neurons against various kinds of insults, and APO-E3 appears to potentiate those beneficial responses.

"APP activation of microglia in the vicinity of brain injury or inflammation has the potential to be detrimental indirectly to the neurons," he continued, "because activated microglia produce things that are toxic to neurons. And it looks as if APO-E3 and APO-E4 are coordinating that balance to some extent, determining whether APP's beneficial or detrimental effects prevail."

Barger observed, "There's a pretty wide variety of things that researchers have picked to be their favorite neurotoxin. One is an excitotoxin, which is an amino acid that tends to trigger a response in a nerve cell, so it produces a signal. And when too much of this neurotransmitter is lying around," he continued, "the neuron becomes hyper-excited, and eventually dies. It's too much of a good thing, I guess."

The part played by APP in the formation of senile neuritic amyloid plaques as a causative factor in AD, Barger suggested, "may be a loaded question. The relevance of plaques to the symptoms of the disease is disputed, so we're not quite sure whether they actually cause the pathology."

Rodent Brain Cells Model Microglial Havoc

An alternative etiology, he suggested, "may be that the symptoms arise from a more diffuse cell-by-cell loss of function, which could result from the neurotoxic milieu that the microglia are setting up."

Barger used cultures of rat microglial cells in experiments assessing "what microglia do when they're turned on in inflammatory situations."

One thing they do, he determined, "is accumulate nitrite [NO₂], a simple measure of the gaseous neurotransmitter, nitric oxide [NO], being produced. And depending on conditions, NO can have either good or bad effects on the neurons."

Microglial cells in the brain are molecular variants of the immune system's white blood cells, macrophages and monocytes. Like these, Barger pointed out, "one of microglia's debris-scavenging functions is to clean up after some sort of brain injury, which turns them on. But if their activation," he went on, "is perpetuated beyond its usefulness, then the microglia may become damaging."

In the rodent microglial cell culture, he confirmed that treatment with APP raised the level of a transcription factor, NFkappaB, which goes up when brain inflammation incites APP to activate the microglia.

"The final thing our experiments looked at," Barger recounted, "was an indirect measure of neurotoxicity. So we used a combined culture of microglia with neurons and assessed the effects of APP, via the microglia, on neuronal health.

"One of the most compelling arguments to be made in this connection between brain injury and development of AD is that, because APP is elevated in various kinds of brain injury, presumably it would also trigger elevation of microglial activity. That would probably not be too healthy for the neurons. And once a neuron's health is compromised, or it even dies, certainly you have loss of function.

"Depending on the brain regions in which that occurs," he pointed out, "the type of cell affected, it could easily be manifest as a loss of memory, and the other kinds of cognitive deficits that occur in AD."

Strategies For Finding Anti-AD Therapeutics

Following up on these insights, he continued, "We're now trying to characterize the neurotoxins produced by the microglia that are relevant in this model, to determine if there are potential therapeutic interventions there. Perhaps we can design drug strategies to block those activities."

Pending such prospective anti-AD drug discoveries, Barger made the point that "there are already some promising studies showing benefit from anti-inflammatory drugs. Simple nonsteroidal anti-inflammatory compounds, such as ibuprofen, show some benefit in the prevention of AD and/or slowing its progression.

"So if we can design agents, for instance, that work better on microglia than they do on some of the other inflammatory cells of the body, or that specifically block the kind of reaction that microglia have in AD," Barger concluded, "it may be a simple case of tweaking the drugs in a way that makes them more active in this specific scenario." *