Strong evidence has implicated synaptic failure as a direct contributor to cognitive decline in Alzheimer's disease (AD), and selenium (Se) supplementation has demonstrated potential for AD treatment. However, the exact roles of Se and related selenoproteins in mitigating synaptic deficits remain unclear.
Results:
Our data show that selenomethionine (Se-Met), as the major organic form of Se in vivo, structurally restored synapses, dendrites, and spines, leading to improved synaptic plasticity and cognitive function in triple transgenic AD (3 × Tg-AD) mice. Furthermore, we found that Se-Met ameliorated synaptic deficits by inhibiting extrasynaptic N-methyl-d-aspartate acid receptors (NMDARs) and stimulating synaptic NMDARs, thereby modulating calcium ion (Ca2+) influx. We observed that a decrease in selenoprotein K (SELENOK) levels was closely related to AD, and a similar disequilibrium was found between synaptic and extrasynaptic NMDARs in SELENOK knockout mice and AD mice. Se-Met treatment upregulated SELENOK levels and restored the balance between synaptic and extrasynaptic NMDAR expression in AD mice.
Innovation:
These findings establish a key signaling pathway linking SELENOK and NMDARs with synaptic plasticity regulated by Se-Met, and thereby provide insight into mechanisms by which Se compounds mediate synaptic deficits in AD.
Conclusion:
Our study demonstrates that Se-Met restores synaptic deficits through modulating Ca2+ influx mediated by synaptic and extrasynaptic NMDARs in 3 × Tg-AD mice, and suggests a potentially functional interaction between SELENOK and NMDARs. Antioxid. Redox Signal. 35, 863–884.
Get full access to this article
View all access options for this article.
References
1.
AgarwalS, TannenbergRK, and DoddPR. Reduced expression of the inhibitory synapse scaffolding protein gephyrin in Alzheimer's disease. J Alzheimers Dis, 14: 313–321, 2008.
2.
AkbaralyTN, Hininger-FavierI, CarriereI, ArnaudJ, GourletV, RousselAM, and BerrC. Plasma selenium over time and cognitive decline in the elderly. Epidemiology, 18: 52–58, 2007.
3.
AlberdiE, Sanchez-GomezMV, CavaliereF, Perez-SamartinA, ZugazaJL, TrullasR, DomercqM, and MatuteC. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium, 47: 264–272, 2010.
4.
BezprozvannyI and MattsonMP. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci, 31: 454–463, 2008.
5.
BlissTV and CollingridgeGL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361: 31–39, 1993.
6.
BrigmanJL, WrightT, TalaniG, Prasad-MulcareS, JindeS, SeaboldGK, MathurP, DavisMI, BockR, GustinRM, ColbranRJ, AlvarezVA, NakazawaK, DelpireE, LovingerDM, and HolmesA. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci, 30: 4590–4600, 2010.
7.
BulteauAL and ChavatteL. Update on selenoprotein biosynthesis. Antioxid Redox Signal, 23: 775–794, 2015.
8.
CalabreseB, WilsonMS, and HalpainS. Development and regulation of dendritic spine synapses. Physiology (Bethesda), 21: 38–47, 2006.
9.
CalabreseV, CorneliusC, Dinkova-KostovaAT, CalabreseEJ, and MattsonMP. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal, 13: 1763–1811, 2010.
10.
CalabreseV, SantoroA, Trovato SalinaroA, ModafferiS, ScutoM, AlbouchiF, MontiD, GiordanoJ, ZappiaM, FranceschiC, and CalabreseEJ. Hormetic approaches to the treatment of Parkinson's disease: perspectives and possibilities. J Neurosci Res, 96: 1641–1662, 2018.
11.
CardosoBR, OngTP, Jacob-FilhoW, JaluulO, FreitasMI, and CozzolinoSM. Nutritional status of selenium in Alzheimer's disease patients. Br J Nutr, 103: 803–806, 2010.
12.
ChoiDW. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett, 58: 293–297, 1985.
13.
Concetta ScutoM, MancusoC, TomaselloB, Laura OntarioM, CavallaroA, FrascaF, MaiolinoL, Trovato SalinaroA, CalabreseEJ, and CalabreseV. Curcumin, hormesis and the nervous system. Nutrients, 11: 2417, 2019.
14.
DeKoskyST and ScheffSW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol, 27: 457–464, 1990.
15.
DuS, ZhouJ, JiaY, and HuangK. SelK is a novel ER stress-regulated protein and protects HepG2 cells from ER stress agent-induced apoptosis. Arch Biochem Biophys, 502: 137–143, 2010.
16.
DumasTC. Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning. Prog Neurobiol, 76: 189–211, 2005.
17.
DunaevskyA, TashiroA, MajewskaA, MasonC, and YusteR. Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A, 96: 13438–13443, 1999.
18.
EngertF and BonhoefferT. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature, 399: 66–70, 1999.
19.
FosterTC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell, 6: 319–325, 2007.
20.
FredericksGJ, HoffmannFW, RoseAH, OsterheldHJ, HessFM, MercierF, and HoffmannPR. Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. Proc Natl Acad Sci U S A, 111: 16478–16483, 2014.
21.
GrynkiewiczG, PoenieM, and TsienRY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem, 260: 3440–3450, 1985.
22.
GwonAR, ParkJS, ParkJH, BaikSH, JeongHY, HyunDH, ParkKW, and JoDG. Selenium attenuates A beta production and A beta-induced neuronal death. Neurosci Lett, 469: 391–395, 2010.
23.
HardinghamGE and BadingH. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci, 11: 682–696, 2010.
24.
HardinghamGE, FukunagaY, and BadingH. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci, 5: 405–414, 2002.
25.
HoggS. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav, 54: 21–30, 1996.
26.
HsuWL, MaYL, HsiehDY, LiuYC, and LeeEH. STAT1 negatively regulates spatial memory formation and mediates the memory-impairing effect of Abeta. Neuropsychopharmacology, 39: 746–758, 2014.
HuangDW, ShermanBT, TanQ, KirJ, LiuD, BryantD, GuoY, StephensR, BaselerMW, LaneHC, and LempickiRA. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res, 35: W169–W175, 2007.
29.
HuangY, ShenW, SuJ, ChengB, LiD, LiuG, ZhouWX, and ZhangYX. Modulating the balance of synaptic and extrasynaptic NMDA receptors shows positive effects against amyloid-beta-induced neurotoxicity. J Alzheimers Dis, 57: 885–897, 2017.
30.
IsholaIO, AdamsonFM, and AdeyemiOO. Ameliorative effect of kolaviron, a biflavonoid complex from Garcinia kola seeds against scopolamine-induced memory impairment in rats: role of antioxidant defense system. Metab Brain Dis, 32: 235–245, 2017.
31.
IshratT, ParveenK, KhanMM, KhuwajaG, KhanMB, YousufS, AhmadA, ShrivastavP, and IslamF. Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Res, 1281: 117–127, 2009.
32.
JiangT, YuJT, ZhuXC, ZhangQQ, TanMS, CaoL, WangHF, ShiJQ, GaoL, QinH, ZhangYD, and TanL. Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Mol Neurobiol, 51: 220–229, 2015.
33.
KryukovGV, CastellanoS, NovoselovSV, LobanovAV, ZehtabO, GuigoR, and GladyshevVN. Characterization of mammalian selenoproteomes. Science, 300: 1439–1443, 2003.
34.
LawAJ, WeickertCS, WebsterMJ, HermanMM, KleinmanJE, and HarrisonPJ. Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. Eur J Neurosci, 18: 1197–1205, 2003.
35.
LiC, BrakeWG, RomeoRD, DunlopJC, GordonM, BuzescuR, MagarinosAM, AllenPB, GreengardP, LuineV, and McEwenBS. Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice. Proc Natl Acad Sci U S A, 101: 2185–2190, 2004.
36.
LiM, ChengW, NieT, LaiH, HuX, LuoJ, LiF, and LiH. Selenoprotein K mediates the proliferation, migration, and invasion of human choriocarcinoma cells by negatively regulating human chorionic gonadotropin expression via ERK, p38 MAPK, and Akt signaling pathway. Biol Trace Elem Res, 184: 47–59, 2018.
MalenkaRC and BearMF. LTP and LTD: an embarrassment of riches. Neuron, 44: 5–21, 2004.
39.
MarvinJS, BorghuisBG, TianL, CichonJ, HarnettMT, AkerboomJ, GordusA, RenningerSL, ChenTW, BargmannCI, OrgerMB, SchreiterER, DembJB, GanWB, HiresSA, and LoogerLL. An optimized fluorescent probe for visualizing glutamate neurotransmission. Nat Methods, 10: 162–170, 2013.
40.
PetraliaRS. Distribution of extrasynaptic NMDA receptors on neurons. ScientificWorldJournal, 2012: 267120, 2012.
41.
RaymanMP. The importance of selenium to human health. Lancet, 356: 233–241, 2000.
42.
SelkoeDJ. Alzheimer's disease is a synaptic failure. Science, 298: 789–791, 2002.
43.
SolovyevND. Importance of selenium and selenoprotein for brain function: from antioxidant protection to neuronal signalling. J Inorg Biochem, 153: 1–12, 2015.
44.
SongG, ZhangZ, WenL, ChenC, ShiQ, ZhangY, NiJ, and LiuQ. Selenomethionine ameliorates cognitive decline, reduces tau hyperphosphorylation, and reverses synaptic deficit in the triple transgenic mouse model of Alzheimer's disease. J Alzheimers Dis, 41: 85–99, 2014.
45.
Spires-JonesTL, Meyer-LuehmannM, OsetekJD, JonesPB, SternEA, BacskaiBJ, and HymanBT. Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model. Am J Pathol, 171: 1304–1311, 2007.
46.
SuJ, ZhangT, WangK, ZhuT, and LiX. Autophagy activation contributes to the neuroprotection of remote ischemic perconditioning against focal cerebral ischemia in rats. Neurochem Res, 39: 2068–2077, 2014.
47.
TaiDJ, HsuWL, LiuYC, MaYL, and LeeEH. Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning. EMBO J, 30: 205–220, 2011.
48.
TaiHC, Serrano-PozoA, HashimotoT, FroschMP, Spires-JonesTL, and HymanBT. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol, 181: 1426–1435, 2012.
ThibaultO, GantJC, and LandfieldPW. Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store. Aging Cell, 6: 307–317, 2007.
52.
TrapnellC, PachterL, and SalzbergSL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics, 25: 1105–1111, 2009.
53.
van EerselJ, KeYD, LiuX, DelerueF, KrilJJ, GotzJ, and IttnerLM. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc Natl Acad Sci U S A, 107: 13888–13893, 2010.
54.
VermaS, HoffmannFW, KumarM, HuangZ, RoeK, Nguyen-WuE, HashimotoAS, and HoffmannPR. Selenoprotein K knockout mice exhibit deficient calcium flux in immune cells and impaired immune responses. J Immunol, 186: 2127–2137, 2011.
55.
WalshDM, KlyubinI, FadeevaJV, CullenWK, AnwylR, WolfeMS, RowanMJ, and SelkoeDJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416: 535–539, 2002.
56.
WangH and PengRY. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity. Mil Med Res, 3: 26, 2016.
57.
WangR and ReddyPH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis, 57: 1041–1048, 2017.
58.
WirthsO, BreyhanH, MarcelloA, CotelMC, BruckW, and BayerTA. Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging, 31: 747–757, 2010.
59.
WongM and GuoD. Dendritic spine pathology in epilepsy: cause or consequence?. Neuroscience, 251: 141–150, 2013.
60.
XieY, LiuQ, ZhengL, WangB, QuX, NiJ, ZhangY, and DuX. Se-methylselenocysteine ameliorates neuropathology and cognitive deficits by attenuating oxidative stress and metal dyshomeostasis in Alzheimer model mice. Mol Nutr Food Res, 62: e1800107, 2018.
61.
XieY, TanY, ZhengY, DuX, and LiuQ. Ebselen ameliorates beta-amyloid pathology, tau pathology, and cognitive impairment in triple-transgenic Alzheimer's disease mice. J Biol Inorg Chem, 22: 851–865, 2017.
62.
XiongS, MarkesberyWR, ShaoC, and LovellMA. Seleno-L-methionine protects against beta-amyloid and iron/hydrogen peroxide-mediated neuron death. Antioxid Redox Signal, 9: 457–467, 2007.
63.
YangG, PanF, and GanWB. Stably maintained dendritic spines are associated with lifelong memories. Nature, 462: 920–924, 2009.
64.
YusteR and BonhoefferT. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci, 24: 1071–1089, 2001.
65.
ZhangY, ChoYY, PetersenBL, ZhuF, and DongZ. Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. Carcinogenesis, 25: 1165–1175, 2004.
66.
ZhangZH, ChenC, WuQY, ZhengR, LiuQ, NiJZ, HoffmannPR, and SongGL. Selenomethionine reduces the deposition of beta-amyloid plaques by modulating beta-secretase and enhancing selenoenzymatic activity in a mouse model of Alzheimer's disease. Metallomics, 8: 782–789, 2016.
67.
ZhangZH, WuQY, ChenC, ZhengR, ChenY, LiuQ, NiJZ, and SongGL. Selenomethionine Attenuates the amyloid-beta level by both inhibiting amyloid-beta production and modulating autophagy in neuron-2a/AbetaPPswe cells. J Alzheimers Dis, 59: 591–602, 2017.
68.
ZhangZH, WuQY, ZhengR, ChenC, ChenY, LiuQ, HoffmannPR, NiJZ, and SongGL. Selenomethionine mitigates cognitive decline by targeting both tau hyperphosphorylation and autophagic clearance in an Alzheimer's disease mouse model. J Neurosci, 37: 2449–2462, 2017.
69.
ZhengR, ZhangZH, ChenC, ChenY, JiaSZ, LiuQ, NiJZ, and SongGL. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3beta-Wnt pathway in a mouse model of Alzheimer's disease. Biochem Biophys Res Commun, 485: 6–15, 2017.
70.
ZuoY, YangG, KwonE, and GanWB. Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex. Nature, 436: 261–265, 2005.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
