By David N. Leff

Adding irony to injury, it now appears that amyloid precursor protein (APP) — the mother-molecule that spawns senile neuritic plaques in Alzheimer's disease — is itself a memory booster.

APP is a lengthy, bulky, dicey molecule, composed of some 700 amino acids. APP's main claim to fame — infamy, actually — is that it breaks off a small fragment of its chain, amyloid-beta peptide, the basic building block of the fibrillary plaques that pile up between brain cells involved in learning and memory.

Whether these plaques are the perpetrators of memory and cognition loss in Alzheimer's disease (AD), or merely co-conspirators, is still an open question. But it's a solid fact that the only sure way of diagnosing AD, as distinct from other senile dementias, is finding the telltale plaques post mortem in the brain. (See BioWorld Today, May 21, 1998, p. 1.)

"No one knows why APP clips off that neurotoxic amyloid-beta sequence," observed French neurobiologist Arielle Ungerer. "It's supposed that it's one form of break that leads to formation of the plaque-forming amyloid-beta peptide. Other fragments of APP do not." Ungerer is a research director at CNRS (National Center of Scientific Research), in Strasbourg, France, and a faculty member of the affiliated Louis Pasteur University.

Neuroscientist Steven Paul is vice-president of Lilly Research Laboratories, in Indianapolis.

He and Ungerer are co-senior authors of a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated Oct. 13, 1998. Its title is, "Memory-enhancing effects of secreted forms of the ß-amyloid precursor protein in normal and amnestic [forgetful] mice."

The seemingly paradoxical stretch from amyloid-beta's expunging of memory in AD to APP as a memory sharpener has a basis in recent research history, Ungerer told BioWorld Today. "Previous work by others showed," she recounted, "that antibody raised against the soluble, secreted forms of APP was amnesic — causing amnesia. Therefore, it could be said that these forms of APP had a role in learning and memory processes."

Paul added, "APP is a protein of which the processing has been shown to be potentially important for the pathogenesis of AD. Now, the other part of its molecule may be important for various memory processes, in a potentially therapeutic way."

"So, in collaboration with Steven Paul at Lilly," Ungerer continued, "we undertook to test this APP's effect on memory in mice." (Lilly funded the French study.)

"We here at Lilly," Paul recalled, "helped conceptualize the experiment. We synthesized the APP protein, and then asked Ungerer and her people to collaborate with us, because they're experts on memory studies in mice, particularly placing proteins in the lateral ventricle of their brains. Those are not easy experiments to do."

Rodents On APP Got A's In Memory Retention

Ungerer's classroom of French mice faced a heady curriculum of Memory 101 training tasks. Two examples:

Go-No-Go Visual Discrimination: Animal cohorts were trained on two parallel runways, one black, the other white, with food rewards at the end of one. After memorizing these options, they got a mini-dose of APP delivered by minute needles aimed into the cerebral ventricle of the brain. Control mice got saline.

At the same time, all animals were injected under the skin with a dose of scopolamine, an amnesic drug that mimics the cognitive effects of AD. (In recent years, women giving birth have received "twilight sleep" through a concoction of scopolamine and morphine. When they awoke, they had no recollection of labor pains.)

APP administered after the first mouse training session significantly improved their memory performance during the second and third rounds.

Object-Recognition Task: Based on the tendency of rodents to explore a novel object, this test exposed them to a glass marble and a plastic die, and then measured their ability to remember the objects some hours later, under the influence of APP and scopolamine.

"This is an interesting trial," Ungerer recounted, "because it is quite like some tests used in human neuropsychology. Mice treated with APP remembered the object of interest longer than the control animals did. Forgetting occurred later in treated than in controls. That was our first result.

"The second result was that the form of memory is deeply impaired by administration of scopolamine, which is an anti-cholinergic agent. And that APP reverses the amnesia caused by scopolamine.

Clinical Applications 'Not For Tomorrow'

"I also find it interesting," Ungerer went on, "because we added the substances at very, very low doses. As these were administered by intracerebral injections, we now have many verifications to do. The first is to determine what part of the APP molecule is active in memory enhancement."

Ungerer also pointed out that the researchers' work "is the first to show, and the strongest evidence that, APP may also have a role in learning and memory processes."

Anent this prospect of future memory-enhancing drugs, Paul said, "If you can figure out the mechanisms by which APP works — a receptor, for example — you could possibly design a small-molecule compound that would get through the blood-brain barrier, and enhance memory. We have work under way now in that direction. And, by the way, this research and development is going on not just at Lilly and other companies, but in the academic community as well. I suspect that our PNAS paper will spur even greater efforts by various labs to figure this out.

"The clinical applications are not for tomorrow," Ungerer concluded. "But I think it is a new field of research that may be very fruitful." *