Protein Linked to Alzheimer’s Memory Loss

An important clue to the cause of memory loss associated with Alzheimer’s disease has been discovered by researchers at City of Hope in Duarte.

Biochemist Eugene Roberts and his City of Hope colleagues report today in the prestigious Proceedings of the National Academy of Sciences that injections of fragments of a brain protein called beta-amyloid into the brains of mice cause the animals to forget tasks they have just learned.

Researchers have long known that beta-amyloid is present in protein deposits in the brains of Alzheimer’s victims, but they have never been sure whether the protein causes the disease or is simply the byproduct of some other disease process.

The new findings are the first evidence for behavioral changes caused by the protein in living animals and could eventually open the door to the development of new techniques to prevent memory loss in the age-related disorder.

The latest results are “pretty incredible” because scientists have tried for years to find such effects caused by the protein, said molecular biologist Rachael Neve of UC Irvine. “This is really the first correlation between the presence of the (protein) in the brain and the loss of memory.”

The new findings come on the heels of recent discoveries by Neve and by neurologist Bruce A. Yankner of Children’s Hospital in Boston that fragments of the beta-amyloid protein can cause degeneration of brain cells both in the test tube and in rodents. Together, the results provide strong evidence that accumulation of the protein in the brain is a primary cause of Alzheimer’s.

Alzheimer’s is a devastating, progressive brain disorder that affects at least two million Americans, and perhaps as many as four million, most of them over the age of 65. An estimated 250,000 new cases are diagnosed each year.

In its early stages, the disorder may cause subtle memory loss, problems in using language and spatial disorientation. When the disease becomes severe, it causes marked memory loss and impaired thought processes and often leads to incapacitation and death. The cause is not known and no effective treatment has been found.

When the brains of Alzheimer’s victims are autopsied, they are found to contain a dense concentration of so-called neurofibrillary tangles (tangled nerve cell fibers) and neuritic plaques (dense, insoluble deposits of proteins and other materials). The primary protein component of the plaques is beta-amyloid, but researchers have been unable to reach a consensus on whether the plaques simply represent detritus from the death of brain cells caused by Alzheimer’s or whether they themselves cause the disease.

Many researchers now believe that beta-amyloid is a breakdown product of a larger protein, called amyloid precursor protein, or APP, that plays a crucial role in brain cells, as well as in cells elsewhere in the body. The nature of that normal function is still a mystery, but some studies by Yankner and neurologist Carl Cotman of UC Irvine suggest that APP may stimulate growth and regeneration of nerve cells.

After its function in the cell is completed, APP would normally be broken down into its components by cellular enzymes, which would then use those components to build other proteins. Some researchers, such as Roberts, speculate that aging cells are missing one or more of the enzymes necessary for destroying APP, so that large fragments are left behind to cause neurological damage.

Roberts and biologists James F. Flood and John E. Morley of the Veterans Administration Medical Center in St. Louis were able to show that fragments of beta-amyloid were capable of causing memory loss by working with several groups of 15 mice trained to avoid having their feet shocked in a device called a T-maze.

The mice were placed in one end of the 1 1/2-foot-long device and trained to go rapidly into one of two boxes at the T-end after a bell sounds. If they did not make it within five seconds, their feet received a mild shock until they entered the box.

The researchers injected the beta-amyloid fragments, called peptides, into the brains of the mice within 24 hours after they were trained in using the T-maze, then tested them again a week later. They found that increasing quantities of the peptides made the mice more likely to forget their training. In control experiments, mice injected with only the fluid used to dissolve the peptides suffered no memory loss.

The peptides had an effect only when the mice’s brains were processing the training from short-term memory to long-term memory, a process called consolidation. This is the aspect of memory that is also hit hardest by Alzheimer’s. The peptides did not cause amnesia when injected more than 24 hours after the training, and they did not affect the storage or retrieval of older memories.

The effect was observed when the peptides were injected into ventricles, fluid-filled spaces in the brain, but was strongest when they were injected directly into the hippocampus. The hippocampus is a brain structure that plays a crucial role in learning and memory, and always shows severe pathological change and the highest concentration of plaque in Alzheimer’s victims.

Roberts and Flood hope to learn precisely where in the cell the peptides are acting. It may then be possible, Roberts said, to devise drugs that would block the interaction and thereby delay or prevent the memory loss associated with Alzheimer’s.

“Frankly, we’re very excited about it (the results),” Roberts said, but he urged caution in interpreting the findings because they might be simply fortuitous. However, the results are so striking, he said, that “as soon as the paper comes out, hundreds of people will start trying to repeat the results. . . . Is it just a set of interesting observations, or is it something that is really important? That will be settled soon because there is a lot of interest in it.”