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Lamotrigine Reduces ß-Site AßPP-Cleaving Enzyme 1 Protein Levels Through Induction of Autophagy.
Wu, Hao; Lu, Mei-Hong; Wang, Wang; Zhang, Mao-Ying; Zhu, Qian-Qian; Xia, Yi-Yuan; Xu, Ru-Xiang; Yang, Yi; Chen, Li-Hua; Ma, Quan-Hong.
Afiliación
  • Wu H; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
  • Lu MH; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
  • Wang W; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
  • Zhang MY; Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
  • Zhu QQ; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
  • Xia YY; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
  • Xu RX; Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
  • Yang Y; Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
  • Chen LH; Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
  • Ma QH; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
J Alzheimers Dis ; 46(4): 863-76, 2015.
Article en En | MEDLINE | ID: mdl-25854934
Lamotrigine (LTG), a broad-spectrum anti-epileptic drug widely used in treatment for seizures, shows potential efficacy in Alzheimer's disease (AD) therapy. Chronic LTG treatment rescues the suppressed long-term potentiation, loss of spines and cognitive deficits in AßPP/PS1 mice, known to overexpress a chimeric mouse/human mutant amyloid-ß protein precursor (AßPP) and a mutant human presenilin 1 (PS1). These changes are accompanied by reduction of amyloid-ß (Aß) plaques density and of levels of ß-C-terminal fragment of AßPP (ß-CTF), a fragment of AßPP cleaved by ß-secretase. These results suggest LTG treatment reduces Aß production, possibly through modulation of cleavage of AßPP by ß-secretase. However, the underlying mechanisms still remain unclear. In this study, decreased protein levels, but not mRNA levels of ß-site AßPP-cleaving enzyme 1 (BACE1), were observed in cultured HEK293 cells and the brains of AßPP/PS1 transgenic mice upon LTG treatment. Moreover, LTG treatment suppressed mammalian target of rapamycin (mTOR) signaling, while enhancing activation of cAMP response element binding protein (CREB), two signaling pathways essential for autophagy induction. LTG treatment increased the numbers of LC3-GFP + puncta and LC3-II levels in HEK293 cells, indicating an induction of autophagy. The downregulation of BACE1 by LTG treatment was prevented by the autophagy inhibitor 3-Methyladenine. Therefore, this study shows that LTG treatment reduces the protein levels of BACE1 through activation of autophagy, possibly via inhibition of mTOR signaling and activation of CREB.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Triazinas / Ácido Aspártico Endopeptidasas / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Animals / Humans Idioma: En Revista: J Alzheimers Dis Asunto de la revista: GERIATRIA / NEUROLOGIA Año: 2015 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Triazinas / Ácido Aspártico Endopeptidasas / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Animals / Humans Idioma: En Revista: J Alzheimers Dis Asunto de la revista: GERIATRIA / NEUROLOGIA Año: 2015 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos