Failure to Dephosphorylate Tau Proteins Leads to Alzheimer's Disease

Researchers have shown that Pin1 (prolyl isomerase) is pivotal in protecting against age-dependent neurodegeneration due to its ability to dephosphorylate tau proteins, a finding that provides insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies.

In healthy brains, tau proteins serve to assemble and support the "scaffolding” systems that give neurons their structure and function. Phosphates are routinely added and removed from tau. However, in certain neurodegenerative conditions, such as Alzheimer's disease, excess phosphate molecules cause the protein to change shape and cluster into fibers that become tangled and knotted, forming rigid structures that eventually lead to the destruction of the affected neurons in certain regions of the brain, resulting in symptoms of dementia.

In a study published in the July 31, 2003, issue of Nature, investigators at Harvard Medical School (Boston, MA, USA) reported they had developed a knockout mouse lacking the gene for Pin1. These animals suffered progressive age-dependent neuropathy characterized by motor and behavioral deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. In addition, the researchers compared Pin1 expression profiles in different brain regions of both healthy individuals and patients with Alzheimer's disease.


"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,” explained senior author Dr. Kun Ping Lu, associate professor of medicine at Harvard Medical School. "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. We have now shown that Pin1 plays a pivotal role in protecting against age-dependent neurodegeneration. This makes a convincing case that this enzyme should be taken into consideration in future studies of Alzheimer's disease.”




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Harvard Medical School