The neuropathological hallmarks of Alzheimer's disease (AD) are tangles made of hyperphosphorylated tau (p- tau) and plaques consisted of Abeta deposits. Tau hyperphosphorylation especially on Ser or Thr residues before Pro (pSer/Thr-Pro) precedes tangle formation. We have recently found that certain pSer/Thr-Pro motifs exist in two distinct cis and trans conformations and identified a unique enzyme, Pin1 that specifically catalyzes their isomerization in vitro. Importantly, Pin1 controls a subset of key regulators to help coordinate their functions and its deregulation can contribute to certain diseases, notably AD. Pin1 acts on the pThr231-Pro motif in p-tau to inhibit tau-related pathology (tauopathy) and on the pThr668-Pro motif in APP to reduce A?- pathology. Pin1 knockout mice develop age-dependent tau- and A?-pathologies, whereas Pin1 overexpression inhibits tauopathy in mice. These results are relevant to human AD because Pin1 is inhibited in MCI and AD neurons by various mechanisms, but preventing Pin1 inhibition is associated with delayed onset of AD. Human Pin1 gene is located to 19p13.2, a new locus associated with late-onset AD. We thus proposed that Pin1 might help protect against neurodegeneration in AD by regulating protein conformations. However, a major challenge is the lack of any tool available that is able to distinguish cis from trans pSer/Thr-Pro conformation in a native protein. Thus there is no direct evidence for the presence of these two p- tau conformations and their conformation-specific functions or regulation in tauopathy. Moreover, whether Pin1 and p-tau conformations play any role in cognitive function relevant to AD is also not known. To address these critical issues, we developed Pin1 conditional knockout mice and a novel technology to generate a first pair of antibodies able to detect specifically cis or trans pThr231-Pro motif in p-tau. Our preliminary results suggest that Pin1 increased cis to trans isomerization of pThr231-tau in vitro and in mice, and that cis, but not trans, pThr231-tau was significantly elevated in MCI brains, and further accumulated in AD. This proposal is designed to test our hypotheses that the pathological p-tau is conformation-specific and that modulating such conformation by Pin1 and others would affect tauopathy and cognitive function relevant to AD.
Aim 1 is to determine which p-tau conformations are pathologicaly more relevant during tauopathy using AD mouse models and human AD samples.
Aim 2 is to determine the impact of modulating p-tau conformations by Pin1 and other methods on tauopathy in mice, and the relationship between Pin1 and tau conformations in human AD, and the mechanisms underlying the Pin1 action in vitro and in cells.
Aim 3 is to use neuron-specific Pin1 knockout or overexpression or other methods to determine the role of Pin1 and p-tau conformations in cognitive function relevant to AD. These experiments would further define the role of Pin1 and its catalyzed conformational changes in AD, and could lead to new strategies for treating tauopathy. These studies would offer the first in vivo approach to study post-phosphorylation conformational regulation.

Public Health Relevance

The incidence of Alzheimer

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG039405-03
Application #
8526332
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Marilyn
Project Start
2011-09-15
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$337,082
Indirect Cost
$143,357
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Balastik, Martin; Zhou, Xiao Zhen; Alberich-Jorda, Meritxell et al. (2015) Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. Cell Rep 13:812-28
Luo, Man-Li; Gong, Chang; Chen, Chun-Hau et al. (2015) The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation. Cell Rep 11:111-24
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
Luo, Man-Li; Gong, Chang; Chen, Chun-Hau et al. (2014) Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res 74:3603-16
Driver, Jane A; Zhou, Xiao Zhen; Lu, Kun Ping (2014) Regulation of protein conformation by Pin1 offers novel disease mechanisms and therapeutic approaches in Alzheimer's disease. Discov Med 17:93-9
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
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-3β (GSK3β) activity: novel mechanism for Pin1 to protect against Alzheimer disease. J Biol Chem 287:6969-73
Yoon, Sung Ok; Park, Dong Ju; Ryu, Jae Cheon et al. (2012) JNK3 perpetuates metabolic stress induced by Aýý peptides. Neuron 75:824-37
Nakamura, Kazuhiro; Kosugi, Isao; Lee, Daniel Y et al. (2012) Prolyl isomerase Pin1 regulates neuronal differentiation via ýý-catenin. Mol Cell Biol 32:2966-78

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