The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles. Increased phosphorylation of proteins notably tau on serine orthreonine preceding a proline (pSer/Thr-Pro) precedes tangle formation and neurodegeneration. Phosphorylation of APP on the Thr668- Pro motif is shown to regulate Ap secretion in vitro, and to be elevated in AD brains. Recently, we found that pSer/Thr-Pro motifs exist in the two distinct cis and trans conformations, whose conversion is drastically slowed down by phosphorylation, but is catalyzed specifically by the prolyl isomerase Pin1. Pin1 binds to certain proteins and regulates their structure and function by isomerizing specific pSer/Thr-Pro motifs. Importantly, Pin1 is highly expressed in most neurons, but is especially low in vulnerable or degenerated neurons in AD. Pin1 binds to and isomerizes the pThr231-Pro motif in tau, thereby restoring its function and promoting its dephosphorylation. As a result, Pin1 knockout in mice causes age-dependent tauopathy phenotype and neurodegeneration. Moreover, we have now shown that Pin1 has profound effects on APP processing and Ap production. Pin1 binds to the pThr668-Pro motif in APP and greatly accelerates its isomerization, regulating the APP intracellular domain between two distinct conformations as visualized by NMR. Whereas Pin1 overexpression reduces Ap secretion from cell cultures, knockout of Pint increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Ap42 in brains in an age-dependent manner, with Ap42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology. Thus Pin1-catalyzed prolyl isomerization is a novel mechanism to regulate APP processing and Ap production, and its deregulation may link both tangle and plaque pathologies. However, it remains unknown how Pin1 regulates APP processing and Ap production and whether Pin1 affects the plaque pathology. To address these questions, Aim 1 will use molecular and cell biology approaches to determine the mechanisms by which Pin1 regulates APP processing and Ap secretion.
Aim 2 will use mouse models to examine the role of Pin1 in the generation of Ap and amyloid pathology. These studies would provide novel insights into the development of AD and related diseases, and may also have novel therapeutic implications. In lay language, we have recently identified a new enzyme important for the development of Alzheimer's disease. In this proposal, we will continue to investigate how this enzyme affects the disease processes and hope to eventually identify new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017870-10
Application #
8068195
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Miller, Marilyn
Project Start
2000-04-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2011
Total Cost
$292,497
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Driver, Jane A; Zhou, Xiao Zhen; Lu, Kun Ping (2015) Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochim Biophys Acta 1850:2069-76
Nakamura, K; Zhou, X Z; Lu, K P (2013) Distinct functions of cis and trans phosphorylated tau in Alzheimer's disease and their therapeutic implications. Curr Mol Med 13:1098-109
Nakamura, Kazuhiro; Zhen Zhou, Xiao; Ping Lu, Kun (2013) Cis phosphorylated tau as the earliest detectable pathogenic conformation in Alzheimer disease, offering novel diagnostic and therapeutic strategies. Prion 7:117-20
Nakamura, Kazuhiro; Greenwood, Alex; Binder, Lester et al. (2012) Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell 149:232-44
Ma, Suk Ling; Pastorino, Lucia; Zhou, Xiao Zhen et al. (2012) Prolyl isomerase Pin1 promotes amyloid precursor protein (APP) turnover by inhibiting glycogen synthase kinase-3? (GSK3?) activity: novel mechanism for Pin1 to protect against Alzheimer disease. J Biol Chem 287:6969-73
Nakamura, Kazuhiro; Kosugi, Isao; Lee, Daniel Y et al. (2012) Prolyl isomerase Pin1 regulates neuronal differentiation via ?-catenin. Mol Cell Biol 32:2966-78
Pastorino, Lucia; Ma, Suk Ling; Balastik, Martin et al. (2012) Alzheimer's disease-related loss of Pin1 function influences the intracellular localization and the processing of A?PP. J Alzheimers Dis 30:277-97
Min, Sang-Hyun; Lau, Alan W; Lee, Tae Ho et al. (2012) Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol Cell 46:771-83
Ma, Suk Ling; Tang, Nelson Leung Sang; Tam, Cindy Woon Chi et al. (2012) A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease. Neurobiol Aging 33:804-13
Liou, Yih-Cherng; Zhou, Xiao Zhen; Lu, Kun Ping (2011) Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends Biochem Sci 36:501-14

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