Your average adult lab mouse (Mus musculus) weighs in at 25 grams to 30 grams. Of that payload, the murine brain tips the scales at one gram. The brain of your average adult human comes in at 1,400 grams.

But don't poor-mouth a mouse's brain. It comes equipped with a cortex, a hippocampus and other cerebral accoutrements also found in humans. But not only are human brains far weightier and more complex, their wiring diagram is far more sophisticated.

Jens Husemann, research physiologist at Columbia University College of Physicians and Surgeons, explained: "Both species, human and mouse, make APP, the amyloid precursor protein, from which is cleaved Amyloid-beta (A-beta) - a shorter fragment of the longer APP. This A-beta in humans is three amino acids different from the mouse A-beta. Human A-beta tends to aggregate; mouse A-beta does not. Therefore, in aged humans you will find those plaques in Alzheimer's disease; in aged mice, no A-beta deposits.

"There are transgenic mice that do develop A-beta plaques," Husemann continued, "but they are genetically engineered. The mice with the human APP developed plaques, and the researchers injected human synthetic A-beta, a protein that led to production of antibodies. These then attacked and dissolved those plaques."

This made it possible in recent years to recruit those fuzzy-minded rodents as animal models for human Alzheimer's disease.

When a person's brain begins to falter late in life, Alzheimer's disease (AD) is the best-known form of dementia. At post mortem, the AD brain displays clumps of Amyloid-beta, cluttering up the neurons of memory and cognition. These senile plaques are not found in the brains of aging mice. Seeing its main chance, Dublin, Ireland-based Elan Corp. plc immunized na ve mice with A-beta protein and injected the resulting antibodies into other rodents, thus rendering their brains resistant to the formation of neuronal plaques. Then researchers moved from preclinical experiments to clinical, and vaccinated some 360 mild to moderate AD patients with the human 42-amino-acid A-beta peptide. That Phase IIa controlled human trial didn't last long.

Abrupt Ending To Putative Human AD Vaccine

Husemann picks up the debacle story. "The failure of the Elan clinical trial," he recalled, "occurred because participants suffered from swelling of the brain and encephalitis - complications that led to halting the trial. Two years ago, Elan and others used a mouse model for AD, immunizing the animal with A-beta peptide, and elicited an immune response. What they found was that the accumulation and deposition of A-beta was significantly reduced in those amyloid-immunized mice. This suggested that an immune response in A-beta leads to clearance of the peptide from the brain.

"Then Elan in South San Francisco tried the same thing in humans," Husemann continued. "After going through all the preclinical work in animals, they immunized humans with the A-beta peptide. That failed because 15 of the patients enrolled in that clinical trial developed those severe side effects. That was about half a year ago. So they had to stop that clinical trial. The way we saw this work was that antibodies to A-beta protein seemed to bind to the plaque, and the microglia - other brain cells - had an option to attack the plaque and remove it from the brain. It didn't work in humans."

Husemann is senior author of an article in Nature Medicine, released online March 3, 2003. It bears the title: "Adult mouse astrocytes degrade amyloid-b in vitro and in situ." He cited three major findings in the paper.

"The first one was that we identified astrocytes as a brain cell that can bind to, internalize and degrade A-beta - at least in vitro. The degradation in the dish," Husemann recounted, "is as follows. We coated glass slides with amyloid protein, seeded the astrocytes on top and incubated that structure for a day. We found that around the astrocytes, the amyloid was removed from the glass, but reappeared inside the cell, which suggested internalization. And after another day of incubation, even that internalized A-beta was gone - totally eliminated from the dish. We went one step further and took brain sections from transgenic mice that developed amyloid plaques in their brain.

"We sliced those brains very thinly, seeded our adult astrocytes on top and incubated them, again for a day. Then we measured the A-beta content in those brain sections - before, with or without astrocyte treatment. Those cells were capable of removing the amyloid protein present in sections from transgenic mice that have A-beta plaques in their brain. So we now have another cell we can work with: stimulate it, activate it and find out by which mechanism these astrocytes remove or clear A-beta.

"Second, we asked why can't exogenous astrocytes, the most abundant cells in the brain, deal with A-beta? There is something wrong with astrocytes in AD patients. They're made in our brains in every nucleated cell, day in and day out, but it does not accumulate in a healthy person. For some reason, in patients with AD, this protein accumulates. So we're asking: Is there something wrong with the astrocytes so they cannot clear the A-beta anymore, which leads to accumulation, and maybe to AD? That pile-up of A-beta actually causes neuronal cell death, resulting dementia, perhaps AD and eventual death."

Neonatal, Adult Cells Side By Side

"Thirdly," Husemann continued, "most neurobiology research is being done with cells from neonatal rats and mice. The neonatal brain is very easy to digest in culture and the cells you want - neurons or astrocytes - are fairly easy to generate. In our paper, we did some side-by-side comparisons - comparing astrocytes generated from adult mouse brains with their neonatal counterparts. We found significant functional differences there.

"We did the degradation on the slides with either adult or neonatal astrocytes. And we found that adult astrocytes were capable of removing the A-beta, but neonatal ones were not. Most of the research today is done with neonatal cells. We did not; we used adult cells. Now we have to figure out which is the better cell to use. Which represents the astrocyte in vivo, in the living brain, better than neonatal cells or adult cells in culture?

"What we are working on right now," Husemann concluded, "is how can we stimulate astrocytes, and possibly microglial cells, to enter the plaque and remove the A-beta protein from the brain?"