A Brief Primer on Pin1, Amyloid Beta, and Alzheimer's

Pin1 is an enzyme, that can twist the joints of proteins in specific places, so that they may change shape. While it has been known that the enzyme Pin1 can prevent the formation of tangles inside neurons in Alzheimer's Disease, it now appears that Pin1 also can block formation of extracellular plaques. Pin1 is a protein of the parvulin family within the peptidyl-prolyl cis-trans isomerase (PPIase) group of proteins and was the first member of this family to be found in humans.

This newsreport from Beth Israel Deaconess Medical Center, Boston, discusses new research findings supporting the protective effect of the enzyme Pin1 against amyloid beta (abeta) plaques (via amyloid precursor protein, APP) and Alzheimer's Disease. The newsreport describes a paper published in Nature.

The researchers, in collaboration with Linda Nicholson at Cornell University, observed through NMR that when APP was phosphorylated (a process in which an extra phosphate is acquired) it became misshapen and could not be easily restored to its original condition. However, once Pin1 was introduced, APP returned to its normal shape – with dramatic speed.

“We had previously proposed that Pin1 was regulating protein function by greatly accelerating structural changes, but this activity had never actually been visualized,” explains Lu. “Now, for the first time, we were able to actually see this process as it occurred.”

Using cell models the authors next went on to examine the effects of Pin1 on Abeta production, says Lu explaining, “We were able to show that while upregulation of Pin1 reduced Abeta generation, removing the Pin1 gene dramatically increased Abeta production by shifting APP processing away from the normal pathway into the pathological pathway.”

....“Because the effects of Pin1 knockout are age-dependent, we compared Abeta levels in the brains of the mice at different ages,” explains Lu. And indeed their results showed that Pin1 knockout again switched APP processing away from the normal pathway into the pathological pathway in the mouse brains. Moreover, he adds, while Pin1 knockout did not significantly change the levels of Abeta40, it did selectively increase levels of insoluble Abeta42 by a significant 30 to 50 percent in two separate mouse models, to an extent that is similar to what would be found in the brains of Alzheimer’s patients and in mouse models of the disease.

The most common cause of dementia among the elderly, Alzheimer’s disease affects an estimated 4 million individuals in the United States, a number that is expected to increase significantly in the coming years with the aging of the baby boomer generation.

“As was earlier shown with tau proteins, it appears that Pin1 acts to restore misshapen amyloid precursor proteins to their original healthy shape, possibly preventing the onset of neurodegeneration and development of dementia,” says D. Stephen Snyder, PhD, of the Etiology of Alzheimer’s Disease program at the National Institute on Aging, which supported this study. “This finding offers important new insights into the molecular events that lead to Alzheimer’s as we work to develop therapies for the treatment of this widespread disease.”

Read the entire report here.

Here is a brief primer on Pin1 with several links to research papers on Pin1. It provides a review by Julian Thorpe of the above paper in Nature by Lu. Here are some excerpts:

"....Lu and colleagues have previously shown that available, soluble Pin1 is depleted in tangle-bearing neurons of AD brain. Very importantly, they also showed that, in vitro, Pin1 could restore the ability of tau to re-associate with, and reconstitute the integrity of, the microtubules. In this latest research, their hypothesis of a potentially neuroprotective role for Pin1 has been strengthened. Not only do they show that there are lower levels of Pin1 protein in susceptible regions of normal human brain, but also that there is an inverse correlation of neuronal Pin1 and tangle content in AD-affected brain. Finally, and most notably, they have shown that aged Pin1 knockout mice have behavioural and motor deficits, neuronal loss and an accumulation of phosphorylated proteins, including tau that forms filaments and assumes a tangle-like conformation.

Overall, this work establishes Pin1 as an important protein in AD and, implicitly, the other tauopathies. Future work should also provide insights into the effects of Pin1 levels on the course of neurodegenerative disease progression through its control of transcription, translation, endocytosis and apoptosis.”

Here is more background on Pin1 from Julian Thorpe. Here is more on Pin1 involvement in amyloid precursor protein proteolysis and plaque formation.

More pieces of the puzzle seem to be falling into place. More potential therapeutic targets. The most fascinating thing about Pin1 appears to be its association with both neurofibrillary tangles (intracellular) and amyloid plaques (extracellular),the major tissue manifestations of Alzheimer's disease.