title: Lamotrigine Reduces β-Site AβPP-Cleaving Enzyme 1 Protein Levels Through Induction of Autophagy.
abstract: 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 AβPP/PS1 mice, known to overexpress a chimeric mouse/human mutant amyloid-β protein precursor (AβPP) and a mutant human presenilin 1 (PS1). These changes are accompanied by reduction of amyloid-β (Aβ) plaques density and of levels of β-C-terminal fragment of AβPP (β-CTF), a fragment of AβPP cleaved by β-secretase. These results suggest LTG treatment reduces Aβ production, possibly through modulation of cleavage of AβPP by β-secretase. However, the underlying mechanisms still remain unclear. In this study, decreased protein levels, but not mRNA levels of β-site AβPP-cleaving enzyme 1 (BACE1), were observed in cultured HEK293 cells and the brains of AβPP/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.
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Hao
authors: H
authors: Wu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Mei-Hong
authors: MH
authors: Lu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Wang
authors: W
authors: Wang
authors: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors: Mao-Ying
authors: MY
authors: Zhang
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Qian-Qian
authors: QQ
authors: Zhu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Yi-Yuan
authors: YY
authors: Xia
authors: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors: Ru-Xiang
authors: RX
authors: Xu
authors: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors: Yi
authors: Y
authors: Yang
authors: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors: Li-Hua
authors: LH
authors: Chen
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Quan-Hong
authors: QH
authors: Ma
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D016466:CHO Cells; D050882:CREB-Binding Protein / Q000378:metabolism; D003412:Cricetulus; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000077213:Lamotrigine; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D014227:Triazines; D049452:Green Fluorescent Proteins; C025946:3-methyladenine; D050882:CREB-Binding Protein; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000225:Adenine; D000077213:Lamotrigine
keywords: Alzheimer’s disease; BACE1; CREB; autophagy; lamotrigine; mTOR