Missing Enzyme May Cause Alzheimer’s Tangles in Brain

Most efforts to get at the root causes of Alzheimer’s disease these days are focused on amyloid plaques in the brain. But perhaps more attention should be directed toward the other major neuropathological hallmark of Alzheimer’s—neurofibrillary tangles in the brain.

The reason? An enzyme called Pin 1 seems capable of preventing the formation of neurofibrillary tangles, and lacking the gene that makes this enzyme, or at least possessing a faulty copy of the gene that makes it, may predispose people to Alzheimer’s, new research suggests.

The research was conducted by Kung Ping Lu, M.D., Ph.D., an associate professor of medicine at Harvard University Medical School, and colleagues and was published in the July 31 Nature.

In healthy brains, a protein called tau both assembles and supports the scaffolding that gives neurons their structure and function. However, in Alzheimer’s disease, tau becomes burdened with excess phosphate molecules, causing the protein to change shape and cluster into fibers. These fibers then form tangles, and these neurofibrillary tangles then destroy the neurons with which they are associated.

In 1995 Lu and his coworkers found, in test-tube experiments, that a particular enzyme was capable of stripping excess phosphate molecules from neurofibrillary-tangle tau and restoring it to its original shape. The enzyme was the Pin 1 (prolyl isomerase) enzyme. This finding made Lu and his colleagues wonder whether the Pin 1 enzyme might prevent the formation of neurofibrillary tangles in the brain, and they set out to see whether that might be the case.

They looked for the presence of the Pin 1 enzyme in various areas of brains taken from 10 deceased Alzheimer’s patients. They found that the brain areas that possessed the enzyme tended not to have neurofibrillary tangles, whereas the brain areas that didn’t possess the enzyme were apt to have them. This finding thus supported their hunch that the Pin 1 enzyme might be capable of preventing neurofibrillary tangles.

The scientists then knocked out, in mice, the gene that makes the Pin 1 enzyme and examined the brains of the mice to determine the consequences. Without a Pin 1 gene, and thus without a Pin 1 enzyme, the mice’s brains had developed neurofibrillary tangles and neuronal degeneration similar to that seen in Alzheimer’s disease. This discovery reinforced their suspicion that the Pin 1 enzyme prevents the formation of neurofibrillary tangles. But it went even further: It suggested that if people don’t have the gene for the Pin 1 enzyme, or perhaps possess a faulty gene for the enzyme, it might predispose them to Alzheimer’s disease.

“We now need to conduct further studies to explore why Pin 1 [enzyme] expression is low in certain vulnerable neurons to understand the relationship between [the gene for] Pin 1 and other genes that are known to be involved in Alzheimer’s disease, and to find ways to increase Pin 1 expression,” Lu said in a press release issued in conjunction with the July 31 Nature report. “Answering these questions could lead to the development of therapies to prevent or slow age-dependent neurodegenerative processes.”

The research was supported by the National Institutes of Health.

An abstract of the study, “Role of the Prolyl Isomerase Pin 1 in Protecting Against Age-Dependent Neurodegeneration,” is posted on the Web at www.nature.com/nature. ▪