Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice

Nam, So Hee; Seo, Su J.; Goo, Jun Seo; Kim, Jee Eun; Choi, Sun; Lee, Hae Ryun; Hwang, In Sik; Jee, Seung Wan; Lee, Su Hae; Bae, Chang Jun; Park, Jung Youn; Kim, Hye Sung; Shim, Sun Bo; Hwang, Dae Youn

doi:10.3892/ijmm.2011.767

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…Among these, the association of Pen-2 with nicastrin and Aph-1 is required for PSEN1-induced endoproteolysis and gamma-secretase activation [ 12 – 15 ]. Although the exact function of Pen-2 still remained unresolved, some gain-of function and loss-of function studies either in vivo or in vitro have documented the critical role of Pen-2 in the activity of gamma-secretase [ 14 , 15 , 35 – 38 ]. In addition to its action on Notch receptor cleavage, gamma-secretase is also responsible for cutting the transmembrane domain of amyloid β-protein precursor to form amyloid β-protein [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase

Lai¹,

Chang²,

Yeh³

et al. 2015

PLoS ONE

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Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase

Lai¹,

Chang²,

Yeh³

et al. 2015

PLoS ONE

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“…Pen-2 −/– mouse embryos exhibited a Notch-deficiency phenotype and Pen-2 −/– MEFs displayed no γ-secretase activity toward APP processing (Bammens et al, 2011 ). Furthermore, overexpression of human Pen-2 in Pen-2 deficient mice recapitulated AD-like symptoms such as increase in Aβ42, behavioral dysfunctions, and feeding defects, underscoring the importance of Pen-2 in γ-secretase activity and AD pathogenesis (Nam et al, 2011 ).…”

Section: γ-Secretase Is Regulated By Its Four Essential Subunitsmentioning

confidence: 90%

Complex regulation of Î³-secretase: from obligatory to modulatory subunits

Gertsik

Chiu

2015

Front. Aging Neurosci.

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γ-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein (APP), catalyzing the formation of amyloid beta (Aβ) peptides that form amyloid plaques, which contribute to Alzheimer’s disease (AD) pathogenesis. γ-Secretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous enzymatic capacity, γ-secretase activity is tightly regulated. This regulation is a function of many cellular entities, including but not limited to the essential γ-secretase subunits, nonessential (modulatory) subunits, and γ-secretase substrates. Regulation is also accomplished by an array of cellular events, such as presenilin (active subunit of γ-secretase) endoproteolysis and hypoxia. In this review we discuss how γ-secretase is regulated with the hope that an advanced understanding of these mechanisms will aid in the development of effective therapeutics for γ-secretase-associated diseases like AD and Notch-addicted cancer.

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“…The animal model for AD was produced by the microinjection of the human Pen-2 gene, a key regulator of γ-secretase complex, into the pronucleus of fertilized eggs as described previously [11]. All animal experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the Pusan National University (Approval No.…”

Section: Methodsmentioning

confidence: 99%

Peroxiredoxin I regulates the component expression of γ-secretase complex causing the Alzheimer's disease

et al. 2011

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Peroxiredoxin I (Prx I) is a member of the peroxiredoxins (Prxs) family, which are antioxidant enzymes that regulate various cellular process via intracellular oxidative signal pathways. In order to investigate the correlation between Prx I and the γ-secretase complex, which causes Alzheimer's disease (AD), the expression level of Prx I was firstly evaluated in an animal model for AD. NSE/hPen-2 transgenic (Tg) mice, which were used as animal model in this study, showed a high level of Pen-2 expression and accumulation of Aβ-42 peptides in the hippocampus of brain. The expression level of Prx I was significantly higher on the mRNA and protein level in the brain of this model, while not change in Prx VI expression was observed. Furthermore, to verify the effect of Prx I on the γ-secretase components in vitro, the expression level of these components was analyzed in the Prx I transfectants. Of the components of the γ-secretase complex, the expression of PS-2 and Pen-2 was lower in the transfectants overexpressing Prx I compared to the vector transfectants. However, the expression of APP, NCT and APH-1 did not change in Prx I transfectants. Therefore, these results suggested that the expression of Prx I may be induced by the accumulation of Aβ-42 peptides and the overexpression of Prx I in neuroblastoma cells may regulate the expression of γ-secretase components.

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Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice

Cited by 6 publications

References 34 publications

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase

Complex regulation of Î³-secretase: from obligatory to modulatory subunits

Peroxiredoxin I regulates the component expression of γ-secretase complex causing the Alzheimer's disease

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