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Last update 08 May 2025

TBXA2R x APP

Last update 08 May 2025

Basic Info

Related Targets

TBXA2RAPP

Drugs associated with TBXA2R x APP

CNDR-51526

Target

APP x TBXA2R

Mechanism

APP inhibitors [+1]

Active Org.-

Originator Org.

University of Pennsylvania

Active Indication-

Inactive Indication

Alzheimer Disease

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TBXA2R x APP

100 Translational Medicine associated with TBXA2R x APP

0 Patents (Medical) associated with TBXA2R x APP

Literatures (Medical) associated with TBXA2R x APP

30 Apr 2008·The Journal of NeuroscienceQ1 · MEDICINE

Thromboxane Receptor Activation Mediates Isoprostane-Induced Increases in Amyloid Pathology in Tg2576 Mice

Q1 · MEDICINE

Article

Author: Leight, Susan N. ; Lee, Virginia M.-Y. ; Zhang, Bin ; Shineman, Diana W. ; Pratico, Domenico

Alzheimer's disease (AD) amyloid plaques are composed of amyloid-β (Aβ) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers ofin vivooxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like Aβ brain pathology. To determine whether isoprostanes increase Aβ production, we delivered isoprostane iPF2α-III into the brains of Tg2576 mice. Although treated mice showed increased brain Aβ levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF2α-III on Aβ. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased Aβ and secreted APP ectodomains. This increase was a result of increasedAPPmRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for α and β secretase proteolytic cleavages, thereby increasing Aβ generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble Aβ, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.

01 Aug 2004·Neurobiology of DiseaseQ2 · MEDICINE

Amyloid β protein impairs motor function via thromboxane A2 in the rat striatum

Q2 · MEDICINE

Article

Author: Sakaguchi, Gaku ; Ishibashi, Chiyomi ; Itoh, Naohiro ; Okamura, Noboru ; Takahara, Yukio ; Katsuura, Goro ; Arimura, Akinori ; Ueda, Keiichi ; Yagami, Tatsurou ; Nakazato, Hitoshi ; Hiramatsu, Yoshiharu ; Sakaeda, Toshiyuki ; Honma, Tsunetoshi

Amyloid beta protein (Abeta) deposits are found in the striatum of patients with Alzheimer disease (AD) showing extrapyramidal motor dysfunction, but neuronal cell loss has not yet been detected. To clarify how Abeta impairs motor function, we analyzed intrastriatally Abeta-injected rats. Unilateral injection of Abeta(25-35) enhanced apomorphine-induced circling in an ipsilateral direction, indicating ipsilateral dysfunction of dopaminergic nigrostriatal pathways. Volumes of lesion in the Abeta(25-35)-injected striata were significantly higher than those in the saline-injected ones. The correlation between lesion volume and circling behavior was close to significance, but slightly too low, suggesting the possible involvement of other factors in the striatal dysfunction. Abeta(25-35) significantly elevated the level of thromboxane A2 (TXA2). A stable TXA2 agonist, U46619, enhanced circling behavior, and TXA2 receptor antagonists attenuated U46619- and Abeta(25-35)-enhanced circling behavior. This study demonstrated that Abeta(25-35) impairs the motor function of dopaminergic neurons via neuronal cell loss and TXA2. It also sheds light on the therapeutic potential of TXA2 receptor blockers for the neurotoxicity of Abeta.

Scientific ReportsQ3 · CROSS-FIELD

Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors

Q3 · CROSS-FIELD

ArticleOA

Author: James, Michael ; Herbst-Robinson, Katie J ; Brunden, Kurt R ; Liu, Li ; Xie, Sharon X ; Yao, Yuemang

AbstractSenile plaques comprised of Aβ peptides are a hallmark of Alzheimer’s disease (AD) brain, as are activated glia that release inflammatory molecules, including eicosanoids. Previous studies have demonstrated that amyloid precursor protein (APP) and Aβ levels can be increased through activation of thromboxane A2-prostanoid (TP) receptors on neurons. We demonstrate that TP receptor regulation of APP expression depends on Gαq-signaling and conventional protein kinase C isoforms. Importantly, we discovered that Gαq-linked prostaglandin E2 and leukotriene D4 receptors also regulate APP expression. Prostaglandin E2 and thromboxane A2, as well as total APP levels, were found to be elevated in the brains of aged 5XFAD transgenic mice harboring Aβ plaques and activated glia, suggesting that increased APP expression resulted from eicosanoid binding to Gαq-linked neuronal receptors. Notably, inhibition of eicosanoid synthesis significantly lowered brain APP protein levels in aged 5XFAD mice. These results provide new insights into potential AD therapeutic strategies.

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