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New Beneficial Role for Amyloid Precursor Protein

Introduction

A common brain protein often associated with the deposition of harmful material in the brains of Alzheimer’s disease patients may actually be essential for normal brain function. This finding will be presented at the 35th annual meeting of the American Society for Cell Biology in Washington, D.C., on December 11, 1995.

Many neuroscientists believe that abnormal synthesis of amyloid precursor protein (APP) leads to amyloid plaques, which are one of the pathological hallmarks of Alzheimer’s disease. Some researchers at the National Institute on Aging’s (NIA’s) Gerontology Research Center now suggest that APP may play an essential role in the repair of brain nerve injuries. The researchers are not certain how APP behaves in normal brains, but they suggest that it may be essential in keeping brain tissue healthy and in boosting the effectiveness of other brain repair factors.

The Study

In order to try to determine whether Alzheimer’s occurs as a result of the buildup of plaques or as the result of the loss of normal APP activity, or both, Dr. William Wallace of NIA and Vahram Haroutunian of the Bronx VA Medical Center and their colleagues looked at the release of APP in rat brains that had been treated to exhibit symptoms seen in Alzheimer’s disease. When they cut off the supply of the neurotransmitter acetylcholine to cortical nerve cells, the cells responded by synthesizing and secreting elevated amounts of APP. This reaction led Drs. Wallace and Haroutunian to speculate that APP plays some role in the ability of nerve cells to recover after an injury or an Alzheimer’s-like condition.

To further test the idea that APP might help nerve cells repair themselves, the researchers looked at rat neuronal cells in a laboratory dish and exposed them to nerve growth factor (NGF). It is known that APP can act like NGF by helping nerve cells extend their neurites, parts of nerve cells used to make connections to other nerve cells. When exposing nerve cells to low amounts of both APP and NGF (neither of which added separately induces many neurites), Dr. Wallace saw the cells respond as if they had been treated with sufficient amounts of NGF to trigger maximal neurite extension. The combination of the two substances was far more effective than expected. To verify this finding, the investigators then treated the cells with only low levels of APP and saw limited neurite production. When these cells next were treated with low levels of NGF, they responded much more vigorously than cells not pretreated with APP. Thus, the investigators speculate that APP appears to prime the cells to respond vigorously to suboptimal levels of NGF.

Implications

Drs. Wallace and Haroutunian also found that injured rat brains responded readily to injected NGF, and the rats partially recovered from Alzheimer’s-like memory defects. However, levels of NGF normally do not increase after an injury, but APP levels do. Thus, they hypothesize that APP may play an essential role in repairing injured nerve cells by increasing the potency of NGF. NIA scientists speculate that, someday, APP could be used as a therapy to help reverse or prevent further deterioration from Alzheimer’s disease.

APP has been implicated in Alzheimer’s disease because people with mutations in the APP gene invariably get the disease. In cases where Alzheimer’s disease occurs in families, it is thought that a mutation in a single amino acid increases the chance that APP will be processed abnormally. Normal synthesis of APP by nerve cells involves cleavage and release from the cell surface, but abnormal cleavage of APP results in a fragment called amyloid beta (A-beta) peptide, which some scientists believe can form tangled masses of A-beta called senile plaques.

With Alzheimer’s disease, one big question for researchers is whether the plaques cause disease or are just remnants of a disease process that has already occurred. This current research contributes a possible answer to this perplexing question.

Working with Dr. Wallace at the NIA’s Gerontology Research Center were Drs. Candan A. Akar, and W. E. Lyons, and at the National Institute of Mental Health, Dr. Ben Wolozin.

Source: National Institute on Aging

Press Release

December 11, 1995