Findings reported in The JCI show that Pin1 overexpression, which usually degrades tau, increases this protein in the P301L mouse model.
Researchers found that the Pin1 (prolyl isomerase) enzyme, which has been implicated in Alzheimer’s, has two distinct effects depending on the tau protein. They thus suggest that the P301L-tau-mutant mice model of Alzheimer’s may be invalid.
Previous work showed that Pin1 could detangle tau. Current studies, however, discovered that in mice with the P301L tau mutant, Pin1 increases tau pathology.
Even though mutations in the gene encoding tau have not been found in individuals with Alzheimer’s, mouse models based on the mutant P301L tau are still preferred, according to senior author, Kun Ping Lu, M.D., Ph.D. These models show robust tau pathology and neurodegeneration
Dr. Lu, a scientist in the division of hematology/oncology at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School, warns against using P301L tau as an Alzheimer’s model, as it may produce diametrically opposite effects.
The research team moderately overexpressed Pin1 in brain cells 10 days after birth. They found that the tau protein degraded much more quickly than it did in normal control mice.
The scientists then went on to cross two mouse models, those that overexpress the Pin1 enzyme and mouse models of Alzheimer’s disease. They discovered that among mice overexpressing the P301L tau mutant, the exact same Pin1 overexpression did not suppress tau stability but exacerbated the tau pathology and neurodegeneration .
Dr. Lu also points out that these studies establish a proof of concept that boosting Pin1 activity may offer a new idea for preventing or even treating the tau pathology and neurodegeneration in Alzheimer’s disease.
The study was conducted by investigators at Beth Israel Deaconess Medical Center, Harvard Medical School, and the University of Pennsylvania School of Medicine. The paper was published in the April 22 advance online issue of The Journal of Clinical Investigation.
