Alzheimer’s disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aβ clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD.
YuF, BronasUG, KonetyS, NelsonNW, DyskenM, JackCJr, WymanJF, VockD, SmithG (2014) Effects of aerobic exercise on cognition and hippocampal volume in Alzheimer’s disease: Study protocol of a randomized controlled trial (The FIT-AD trial). Trials15, 394.
2.
MurakamiK, ShimizuT (2012) Cytoplasmic superoxide radical: A possible contributing factor to intracellular Abeta oligomerization in Alzheimer disease. Commun Integr Biol5, 255–258.
3.
GiannopoulosPF, ChuJ, JoshiYB, SperowM, LiJG, KirbyLG, PraticoD (2013) 5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer’s disease. Biol Psychiatry74, 348–356.
KalraJ, KhanA (2015) Reducing Abeta load and tau phosphorylation: Emerging perspective for treating Alzheimer’s disease. Eur J Pharmacol764, 571–581.
6.
LevineB, KlionskyDJ (2004) Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev Cell6, 463–477.
7.
NahJ, YuanJ, JungYK (2015) Autophagy in neurodegenerative diseases: From mechanism to therapeutic approach. Mol Cells38, 381–389.
8.
TanCC, YuJT, TanMS, JiangT, ZhuXC, TanL (2014) Autophagy in aging and neurodegenerative diseases: Implications for pathogenesis and therapy. Neurobiol Aging35, 941–957.
9.
SalminenA, KaarnirantaK, KauppinenA, OjalaJ, HaapasaloA, SoininenH, HiltunenM (2013) Impaired autophagy and APP processing in Alzheimer’s disease: The potential role of Beclin 1 interactome. Prog Neurobiol106-107, 33–54.
10.
LiL, ZhangS, ZhangX, LiT, TangY, LiuH, YangW, LeW (2013) Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-beta pathology in a mouse model of Alzheimer’s disease. Curr Alzheimer Res10, 433–441.
11.
YangDS, StavridesP, MohanPS, KaushikS, KumarA, OhnoM, SchmidtSD, WessonD, BandyopadhyayU, JiangY, PawlikM, PeterhoffCM, YangAJ, WilsonDA, St George-HyslopP, WestawayD, MathewsPM, LevyE, CuervoAM, NixonRA (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain134, 258–277.
12.
IshratT, ParveenK, KhanMM, KhuwajaG, KhanMB, YousufS, AhmadA, ShrivastavP, IslamF (2009) Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Brain Res1281, 117–127.
13.
DominiakA, WilkaniecA, WroczynskiP, AdamczykA (2016) Selenium in the therapy of neurological diseases. Where is it going?Curr Neuropharmacol14, 282–299.
14.
ZhangZ, ShenX, XuX (2001) [Effects of selenium on the damage of learning-memory ability of mice induced by fluoride]. Wei Sheng Yan Jiu30, 144–146.
15.
MassaadCA, KlannE (2011) Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal14, 2013–2054.
16.
ChenP, WangL, WangY, LiS, ShenL, LiuQ, NiJ (2014) Phosphoproteomic profiling of selenate-treated Alzheimer’s disease model cells. PLoS One9, e113307.
17.
GwonAR, ParkJS, ParkJH, BaikSH, JeongHY, HyunDH, ParkKW, JoDG (2010) Selenium attenuates A beta production and A beta-induced neuronal death. Neurosci Lett469, 391–395.
18.
van EerselJ, KeYD, LiuX, DelerueF, KrilJJ, GotzJ, IttnerLM (2010) Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proc Natl Acad Sci U S A107, 13888–13893.
19.
XiongS, MarkesberyWR, ShaoC, LovellMA (2007) Seleno-L-methionine protects against beta-amyloid and iron/hydrogen peroxide-mediated neuron death. Antioxid Redox Signal9, 457–467.
20.
SongG, ZhangZ, WenL, ChenC, ShiQ, ZhangY, NiJ, LiuQ (2014) Selenomethionine ameliorates cognitive decline, reduces tau hyperphosphorylation, and reverses synaptic deficit in the triple transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis41, 85–99.
21.
ZhangZH, ChenC, WuQY, ZhengR, LiuQ, NiJZ, HoffmannPR, SongGL (2016) Selenomethionine reduces the deposition of beta-amyloid plaques by modulating beta-secretase and enhancing selenoenzymatic activity in a mouse model of Alzheimer’s disease. Metallomics8, 782–789.
22.
SuJ, ZhangT, WangK, ZhuT, LiX (2014) Autophagy activation contributes to the neuroprotection of remote ischemic perconditioning against focal cerebral ischemia in rats. Neurochem Res39, 2068–2077.
23.
JiangT, YuJT, ZhuXC, ZhangQQ, TanMS, CaoL, WangHF, ShiJQ, GaoL, QinH, ZhangYD, TanL (2015) Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Mol Neurobiol51, 220–229.
24.
ChoyRW, ChengZ, SchekmanR (2012) Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid beta (Abeta) production in the trans-Golgi network., E. Proc Natl Acad Sci U S A109, 2077–2082.
25.
WrigleyJD, SchurovI, NunnEJ, MartinAC, ClarkeEE, EllisS, BonnertTP, ShearmanMS, BeherD (2005) Functional overexpression of gamma-secretase reveals protease-independent trafficking functions and a critical role of lipids for protease activity. J Biol Chem280, 12523–12535.
26.
McLelandCB, RodriguezJ, SternST (2011) Autophagy monitoring assay: Qualitative analysis of MAP LC3-I to II conversion by immunoblot. Methods Mol Biol697, 199–206.
DolanPJ, JohnsonGV (2010) The role of tau kinases in Alzheimer’s disease. Curr Opin Drug Discov Devel13, 595–603.
29.
BenjaminD, ColombiM, MoroniC, HallMN (2011) Rapamycin passes the torch: A new generation of mTOR inhibitors. Nat Rev Drug Discov10, 868–880.
30.
ChongZZ, ShangYC, ZhangL, WangS, MaieseK (2010) Mammalian target of rapamycin: Hitting the bull’s-eye for neurological disorders. Oxid Med Cell Longev3, 374–391.
31.
KomatsuM, WaguriS, ChibaT, MurataS, IwataJ, TanidaI, UenoT, KoikeM, UchiyamaY, KominamiE, TanakaK (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature441, 880–884.
32.
KomatsuM, WaguriS, KoikeM, SouYS, UenoT, HaraT, MizushimaN, IwataJ, EzakiJ, MurataS, HamazakiJ, NishitoY, IemuraS, NatsumeT, YanagawaT, UwayamaJ, WarabiE, YoshidaH, IshiiT, KobayashiA, YamamotoM, YueZ, UchiyamaY, KominamiE, TanakaK (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell131, 1149–1163.
33.
AvrahamiL, FarfaraD, Shaham-KolM, VassarR, FrenkelD, Eldar-FinkelmanH (2013) Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: In vivo and in vitro studies. J Biol Chem288, 1295–1306.
34.
ZhouC, ZhongW, ZhouJ, ShengF, FangZ, WeiY, ChenY, DengX, XiaB, LinJ (2012) Monitoring autophagic flux by an improved tandem fluorescent-tagged LC3 (mTagRFP-mWasabi-LC3) reveals that high-dose rapamycin impairs autophagic flux in cancer cells. Autophagy8, 1215–1226.
35.
YaminG, OnoK, InayathullahM, TeplowDB (2008) Amyloid beta-protein assembly as a therapeutic target of Alzheimer’s disease. Curr Pharm Des14, 3231–3246.
36.
KurzA, PerneczkyR (2011) Amyloid clearance as a treatment target against Alzheimer’s disease. J Alzheimers Dis24(Suppl 2), 61–73.
37.
O’ConnorT, SadleirKR, MausE, VelliquetteRA, ZhaoJ, ColeSL, EimerWA, HittB, BembinsterLA, LammichS, LichtenthalerSF, HebertSS, De StrooperB, HaassC, BennettDA, VassarR (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron60, 988–1009.
ZhuZ, YanJ, JiangW, YaoXG, ChenJ, ChenL, LiC, HuL, JiangH, ShenX (2013) Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both beta-amyloid production and clearance. J Neurosci33, 13138–13149.
40.
LeroyK, YilmazZ, BrionJP (2007) Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol33, 43–55.
41.
TangY, HuangD, ZhangMH, ZhangWS, TangYX, ShiZX, DengL, ZhouDH, LuXY (2016) Salvianolic acid B inhibits Abeta generation by modulating BACE1 activity in SH-SY5Y-APPsw cells. Nutrients8, pii: E333.
42.
GuXH, XuLJ, LiuZQ, WeiB, YangYJ, XuGG, YinXP, WangW (2016) The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer’s disease. Behav Brain Res311, 309–321.
43.
TomicJL, PensalfiniA, HeadE, GlabeCG (2009) Soluble fibrillar oligomer levels are elevated in Alzheimer’s disease brain and correlate with cognitive dysfunction. Neurobiol Dis35, 352–358.
44.
HaassC, SelkoeDJ (2007) Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol8, 101–112.
45.
MadeoF, EisenbergT, KroemerG (2009) Autophagy for the avoidance of neurodegeneration. Genes Dev23, 2253–2259.
NguyenHB, BabcockJT, WellsCD, QuilliamLA (2013) LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap. Oncogene32, 4100–4109.
48.
JiangT, YuJT, ZhuXC, ZhangQQ, CaoL, WangHF, TanMS, GaoQ, QinH, ZhangYD, TanL (2014) Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance. Neuropharmacology85, 121–130.
49.
DengH, MiMT (2016) Resveratrol attenuates Abeta25-35 caused neurotoxicity by inducing autophagy through the TyrRS-PARP1-SIRT1 signaling pathway. Neurochem Res41, 2367–2379.
ZhouJ, TanSH, CodognoP, ShenHM (2013) Dual suppressive effect of MTORC1 on autophagy: Tame the dragon by shackling both the head and the tail. Autophagy9, 803–805.
52.
MizushimaN (2007) Autophagy: Process and function. Genes Dev21, 2861–2873.
53.
UrbanelliL, EmilianiC, MassiniC, PersichettiE, OrlacchioA, PelicciG, SorbiS, HasilikA, BernardiG, OrlacchioA (2008) Cathepsin D expression is decreased in Alzheimer’s disease fibroblasts. Neurobiol Aging29, 12–22.
54.
ZhangYD, ZhaoJJ (2015) TFEB participates in the Abeta-induced pathogenesis of Alzheimer’s disease by regulating the autophagy-lysosome pathway. DNA Cell Biol34, 661–668.
55.
ChoSJ, YunSM, JoC, LeeDH, ChoiKJ, SongJC, ParkSI, KimYJ, KohYH (2015) SUMO1 promotes Abeta production via the modulation of autophagy. Autophagy11, 100–112.
56.
ChenRF, ZhangT, SunYY, SunYM, ChenWQ, ShiN, ShenF, ZhangY, LiuKY, SunXJ (2015) Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells. Neural Regen Res10, 1433–1440.
57.
WuH, LuMH, WangW, ZhangMY, ZhuQQ, XiaYY, XuRX, YangY, ChenLH, MaQH (2015) Lamotrigine reduces beta-site AbetaPP-cleaving enzyme 1 protein levels through induction of autophagy. J Alzheimers Dis46, 863–876.
58.
CaiZ, ZhouY, LiuZ, KeZ, ZhaoB (2015) Autophagy dysfunction upregulates beta-amyloid peptides via enhancing the activity of gamma-secretase complex. Neuropsychiatr Dis Treat11, 2091–2099.
59.
LauritzenI, Pardossi-PiquardR, BourgeoisA, PagnottaS, BiferiMG, BarkatsM, LacorP, KleinW, BauerC, CheclerF (2016) Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology. Acta Neuropathol132, 257–276.
60.
PericA, AnnaertW (2015) Early etiology of Alzheimer’s disease: Tipping the balance toward autophagy or endosomal dysfunction?Acta Neuropathol129, 363–381.
