An enzyme called Pin1 can prevent the accumulation of tau protein in brain neurons that characterizes age-dependent Alzheimer’s disease, according to research published in the July 31st issue of Nature. The findings, which offer new insight into Alzheimer’s disease and other neurodegenerative disorders, may eventually lead to new therapies to help prevent and treat these devastating conditions.

“We’ve now shown that Pin1 [prolyl isomerase] plays a pivotal role in protecting against age-dependent neurodegeneration,” said Kun Ping Lu, M.D., Ph.D., the study’s senior author. “This makes a convincing case that this enzyme should be taken into consideration in future studies of Alzheimer’s disease.”

Since the discovery of tangled masses of protein in the neurons of people who died from Alzheimer’s disease, researchers have studied the possibility that gene overexpression was responsible. The current study provides the first genetic evidence that age-dependent neurodegenerative diseases develop from the absence of gene expression.

As background information, Lu discussed the recognition that the characteristic protein tangles were masses of a protein called tau that normally plays a vital role in the assembly and maintenance of neurons’ physical structure. Ordinarily, the tau protein undergoes addition and removal of phosphate groups. In neurodegenerative conditions such as Alzheimer’s disease, the tau protein becomes increasingly phosphorylated over time, and the excess phosphate groups cause the protein to change shape and form tangled masses. The rigidity of neuron structure caused by the protein masses eventually leads to the death of the affected neurons; functionally, this is seen as the progressive symptoms of dementia.

The researchers involved in the current study originally identified the Pin 1 enzyme in 1995 and discovered that it promotes removal of phosphate groups from tau protein, restoring tangled protein to its original shape. In the new work, the group tested their hypothesis on the normal and pathological processes by comparing expression of the Pin 1 gene in different brain regions of healthy adults and people with Alzheimer’s disease. The investigators also created a mouse model to study the consequences of deletion of the Pin1 gene.

They found that Pin1 activity is required to ensure that neurons function normally and do not start the excessive phosphate-group addition that marks neurodegeneration. “Our findings showed that Pin1expression inversely correlates with neuronal vulnerability to degeneration in normal brains, and with the actual formation of tangles in patients with Alzheimer’s,” said Lu. “Furthermore, we found that in the Pin1 knockout mouse, the removal of the Pin1 gene alone was sufficient to cause many age-dependent neurodegenerative changes.”

“Based upon these results, the suggestion that the Pin1 enzyme seems to protect neurons from injury and death renews and sharpens an interest in the control of protein phosphorylation,” commented D. Stephen Snyder, Ph.D., of the Etiology of Alzheimer’s Disease program at the National Institute on Aging, which supported this study. “In so doing, it offers both mechanistic and therapeutic insights useful in developing possible interventions against Alzheimer’s disease.”

“Pin1 represents a new category of genes whose expression is required to guard against age-dependent neurodegeneration,” concluded Lu. “We now need to conduct further studies to explore why Pin1 expression is low in certain vulnerable neurons, to understand the relationship between Pin1 and other genes that are known to be involved in Alzheimer’s disease, and to find ways to increase Pin1 expression. Answering these questions could lead to the development of therapies to prevent or slow age-dependent neurodegenerative processes.”