Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking.
Memantine, an uncompetitive glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as medication for the treatment of Alzheimer's disease (AD). It has been reported that memantine reduces amyloid-β peptide (Aβ) levels in both neuronal cultures and in brains of animal models of AD. However, the underlying mechanism of these effects is unclear. Here we examined the effect of memantine on Aβ production. Memantine was administered to 9-month-old Tg2576 mice, a transgenic mouse model of AD, at 10 or 20mg/kg/day in drinking water for 1 month. Memantine significantly reduced the amounts of both CHAPS-soluble and CHAPS-insoluble Aβ in the brains of Tg2576 mice. Memantine at 10mg/kg/day for 1 month also reduced the levels of insoluble Aβ42 in the brains of aged F344 rats. Moreover, memantine reduced Aβ and sAPPβ levels in conditioned media from rat primary cortical cultures without affecting the enzymatic activities of α-secretase, β-secretase, or γ-secretase. Notably, in a cell-surface biotinylation assay, memantine increased the amount of amyloid precursor protein (APP) at the cell surface without changing the total amount of APP. Collectively, our results indicate that chronic treatment with memantine reduces the levels of Aβ both in AD models and in aged animals, and that memantine affects the endocytosis pathway of APP, which is required for β-secretase-mediated cleavage. This leads to a reduction in Aβ production. These results suggest that memantine reduces Aβ production and plaque deposition through the regulation of intracellular trafficking of APP.
Venture Science Laboratories, R&D Division, Daiichi-Sankyo Co. Ltd., Tokyo 140-8710, Japan. Electronic address: takahashi.kaori.ne@daiichisankyo.co.jp.
Kaori
K
Ito
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: takuyatatebe1215@gmail.com.
Takuya
T
Tatebe
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: suzuxxqpasap@hotmail.com.
Kunimichi
K
Suzuki
Biological Research Department, Daiichi Sankyo RD Novare Co. Ltd., Tokyo 134-8630, Japan. Electronic address: hirayama.takashi.c4@rdn.daiichisankyo.co.jp.
Takashi
T
Hirayama
Biological Research Department, Daiichi Sankyo RD Novare Co. Ltd., Tokyo 134-8630, Japan. Electronic address: hayakawa.maki.yr@rdn.daiichisankyo.co.jp.
Maki
M
Hayakawa
Biological Research Department, Daiichi Sankyo RD Novare Co. Ltd., Tokyo 134-8630, Japan. Electronic address: kubo.hideo@gmail.com.
Hideo
H
Kubo
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: taisuke@mol.f.u-tokyo.ac.jp.
Taisuke
T
Tomita
Venture Science Laboratories, R&D Division, Daiichi-Sankyo Co. Ltd., Tokyo 140-8710, Japan. Electronic address: makino.mitsuhiro.tn@daiichisankyo.co.jp.
Mitsuhiro
M
Makino
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012995:Solubility
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D008559:Memantine
APP; Alzheimer's disease; Aβ; Memantine; Trafficking