Lamotrigine Reduces β-Site AβPP-Cleaving Enzyme 1 Protein Levels Through Induction of Autophagy

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 A beta PP/PS1 mice, known to overexpress a chimeric mouse/human mutant amyloid-beta protein precursor (A beta PP) and a mutant human presenilin 1 (PS1). These changes are accompanied by reduction of amyloid-beta (A beta) plaques density and of levels of beta-C-terminal fragment of A beta PP (beta-CTF), a fragment of A beta PP cleaved by beta-secretase. These results suggest LTG treatment reduces A beta production, possibly through modulation of cleavage of A beta PP by beta-secretase. However, the underlying mechanisms still remain unclear. In this study, decreased protein levels, but not mRNA levels of beta-site A beta PP-cleaving enzyme 1 (BACE1), were observed in cultured HEK293 cells and the brains of A beta PP/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.