Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid- peptides (A) derived from amyloid precursor protein (APP), but their exact relationship remains elusive^{1, 2, 3}. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and A production in vitro^{3, 4, 5}. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the Pin1 prolyl isomerase^{6, 7}. Pin1 has been proposed to regulate protein function by accelerating conformational changes^{7, 8, 9, 10}, but such activity has never been visualized and the biological and pathological significance of Pin1 substrate conformations is unknown⁷. Notably, Pin1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, Pin1 knockout causes tauopathy and neurodegeneration^{8, 9, 11, 12}, and Pin1 promoter polymorphisms appear to associate with reduced Pin1 levels and increased risk for late-onset Alzheimer's disease^{13, 14}. However, the role of Pin1 in APP processing and A production is unknown. Here we show that Pin1 has profound effects on APP processing and A production. We find that Pin1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas Pin1 overexpression reduces A secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble A42 (a major toxic species) in brains in an age-dependent manner, with A42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology¹⁵. Thus, Pin1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and A production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.

1. Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
2. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 804, Taiwan, China
3. Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA
4. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
6. †Present address: Institute of Neurobiology, Fudan University, Shanghai 200433, China
7. *These authors contributed equally to this work

Correspondence to: Kun Ping Lu¹ Correspondence and requests for materials should be addressed to K.P.L. (Email: klu@bidmc.harvard.edu).

Received 21 October 2005 | Accepted 12 December 2005

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