Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2019, Vol. 10 Issue (4) : 756-769     DOI: 10.14336/AD.2018.0912
Orginal Article |
Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions
Zhi-Ying Tian1, Chun-Yan Wang1,*, Tao Wang1, Yan-Chun Li2, Zhan-You Wang1,*
1Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang 110122, China
2Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
Download: PDF(1481 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
Abstract  

Evidence has been accumulating that zinc ions can trigger β-amyloid (Aβ) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer’s disease (AD). Chelating zinc inhibits Aβ aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic Ca2+/Zn2+-binding protein found only in a small number of astrocytes in the normal brain. However, in the AD brain, S100A6 is highly expressed in astrocytes around Aβ plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on Aβ plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased Aβ deposition and S100A6 expression, both reversible by the zinc chelator clioquinol, in the brains of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice. To examine whether exogenous S100A6 could induce Aβ plaque disaggregation through competition for zinc in vitro, we incubated APP/PS1 mouse brain sections with recombinant human S100A6 protein or co-incubated them with human S100A6-expressing cells. Both treatments efficiently reduced the Aβ plaque burden in situ. In addition, treatment with exogenous S100A6 protected cultured COS-7 cells against zinc toxicity. Our results show for the first time that increased S100A6 levels correlate with both Aβ disaggregation and decrease of Aβ plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from Aβ deposition through zinc sequestration.

Keywords S100A6      β-amyloid protein      astrocyte      zinc      Alzheimer’s disease     
Corresponding Authors: Wang Chun-Yan,Wang Zhan-You   
About author:

These authors contributed equally.

Just Accepted Date: 20 September 2018   Issue Date: 01 August 2019
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Zhi-Ying Tian
Chun-Yan Wang
Tao Wang
Yan-Chun Li
Zhan-You Wang
Cite this article:   
Zhi-Ying Tian,Chun-Yan Wang,Tao Wang, et al. Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions[J]. Aging and disease, 2019, 10(4): 756-769.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2018.0912     OR     http://www.aginganddisease.org/EN/Y2019/V10/I4/756
Figure 1.  Confocal images showing the effects of zinc and chelator treatments on S100A6 expression and Aβ aggregation in the APP/PS1 mouse brain

The 9-month-old APP/PS1 mice on high-zinc (Zn), zinc + clioquinol (Zn + CQ), or CQ diet were sacrificed. Age-matched APP/PS1 mice given a standard diet and deionized water were used as the controls (Con). (A) Frozen sections of the brain double immunostained with anti-Aβ (green) and anti-S100A6 (red) antibodies showing the distribution and expression of Aβ (a1-d1) and S100A6 (a2-d2), and their co-localization (a3-d3). Aβ and S100A6 immunostaining show significant co-localization in the brain sections of APP/PS1 mice on a high-zinc diet. The Y-Z images depicted in the right panel indicate the positive immunofluorescence staining after orthogonal sectioning. (B) The intensity of Aβ plaques and Aβ plaques-associated S100A6 immunofluorescence were determined. (C) Atomic absorption spectrum assay was used for the measurement of zinc levels in the cortex. Values are means ± S.E.M. Results were compared by a two-way ANOVA followed by t test (n = 5). **P < 0.01. Scale bars = 20 μm.

Figure 2.  High-zinc diet led to an increase of S100A6 protein expression in the brains of APP/PS1 mice

RT-PCR (A, B) and Western blot (C, D) assay were used to detect the mRNA and protein levels of S100A6, respectively, in the brains of APP/PS1 mice fed with high-zinc, zinc + CQ, or CQ diet. Age-matched APP/PS1 mice administered with standard diet and deionized water served as controls (Con). The results are presented as percentages, and the control is defined as 100%. Values represent means ± S.E.M. Results were compared by a two-way ANOVA followed by t test, **P < 0.01 versus the controls, ## P < 0.01 versus the zinc treatment group (n = 5).

Figure 3.  Recombinant human S100A6 (hS100A6) protein reversed zinc-induced cell toxicity

The MTT assay results show the changes in the cell viability with the addition of indicated concentrations of zinc sulfate (ZnSO4) (A) and different concentrations of hS100A6 protein along with 150 μM of ZnSO4 (B). Cells treated with the vehicle served as controls. Zinquin staining was used to detect zinc in the cells that were incubated with 150 μM ZnSO4 and different concentrations of hS100A6 protein (C). Values are means ± S.E.M. and are representative of at least three independent experiments. Results were compared by one-way ANOVA with post-hoc Fisher’s protected least significant difference (PLSD) test, **P < 0.01. Scale bars = 30 μm.

Figure 4.  Overexpression of hS100A6 mitigated zinc-induced decrease of COS-7 cell viability

COS-7 cells were transfected with pcDNA3.1-hS100A6 before being incubated with zinc sulfate (0 µM, 50 µM, 100 µM, 150 µM and 200 µM) for 12 h. COS-7 cells transfected with pcDNA3.1 vector were used as controls (Con). (A) The S100A6 mRNA levels were evaluated using RT-PCR at 48 and 72 h after transfection. (B) Western blot analyses demonstrated S100A6 protein overexpression in the transfected COS-7 cells and in controls. The levels of S100A6 mRNA and protein were expressed as the ratio of the mean intensity at indicated time to the level at 24 h after transfection. (C) Immunofluorescence staining for S100A6 indicate the representative images S100A6-positive cells (Arrows) confirmed the successful transfection of COS-7 with pcDNA3.1-hS100A6 (c1: 0 h; c2: 24 h; c3: 48h; c4: 72h). (D) MTT and lactate dehydrogenase (LDH) assays were performed to determine cell viability after addition of the indicated concentrations of zinc sulfate. The control was defined as 100%. (E) Intracellular zinc levels were detected using the Zinquin staining. Values are means ± S.E.M. and are representative of at least three independent experiments. Results were compared by one-way ANOVA with post-hoc Fisher’s protected least significant difference (PLSD) test, *P < 0.05; **P < 0.01. Scale bars = 30 μm.

Figure 5.  Recombinant hS100A6 protein contributed to Aβ degradation in brain slices of the APP/PS1 mouse

Brain slices collected from APP/PS1 mouse were incubated in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with recombinant hS100A6 protein for 24 h. Adjacent sections from the same brains incubated in DMEM medium alone were used as controls (Con). Immunohistochemical staining with anti-Aβ antibody demonstrated Aβ protein expression. Representative images indicating the Aβ deposits in the cerebral cortex (A) and hippocampus (B). High-magnification images of representative Aβ-positive staining are shown in the right panels. (C) The Aβ plaque burden were quantified. (D) Aβ42 levels were determined by ELISA assay. The content of Aβ42 was expressed as ng per mg of tissue protein. (E) Thioflavin-S (Thio S) and N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide (TSQ) stainings showed the distribution of fibrillar Aβ and zinc, respectively, in the slices of APP/PS1 mouse brain incubated with hS100A6 protein or medium alone. Values are means ± S.E.M. Results were compared by Student’s t test (n = 4). *P < 0.05, **P < 0.01 versus the controls. Scale bars: A, B = 200 μm, and 20 μm in the high magnification of right panels; D = 20 μm.

Figure 6.  Overexpression of hS100A6 was associated with the clearance of amyloid plaques in brain sections of the APP/PS1 mice

Brain slices and adjacent sections from the same brains collected from APP/PS1 mouse were co-incubated with COS-7 cells transfected with pcDNA3.1-hS100A6 or with pcDNA3.1-hS100A6 empty vector (control, Con), respectively, for 24 h. Representative immunohistochemistry images showing the Aβ plaques in the cerebral cortex (A) and hippocampus (B) of the APP/PS1 mice brain. The right panels depict representative Aβ plaques in high magnification. Quantification of Aβ burden demonstrated a significant decrease in the sections incubated with COS-7 cells expressing hS100A6 compared to controls (C). (D) TSQ fluorescence staining was performed to detect zinc levels in the slices of APP/PS1 mouse brain co-incubated with cells expressing hS100A6 or controls. Values are means ± S.E.M. Results were compared by Student’s t test (n = 4). *P < 0.05, **P < 0.01 versus the controls. Scale bars: A, B = 200 μm, and 20 μm in the high magnification right panels; D = 20 μm.

[1] Eckerstrom C, Klasson N, Olsson E, Selnes P, Rolstad S, Wallin A (2018). Similar pattern of atrophy in early- and late-onset Alzheimer's disease. Alzheimers Dement (Amst), 10: 253-259.
[2] Ding Q, Tanigawa K, Kaneko J, Totsuka M, Katakura Y, Imabayashi E, et al. (2018). Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4. Aging Dis, 9: 334-345.
[3] Guglielmotto M, Monteleone D, Piras A, Valsecchi V, Tropiano M, Ariano S, et al. (2014). Abeta1-42 monomers or oligomers have different effects on autophagy and apoptosis. Autophagy, 10: 1827-1843.
[4] Szybinska A, Lesniak W (2017). P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes? Aging Dis, 8: 506-518.
[5] Bearer EL, Manifold-Wheeler BC, Medina CS, Gonzales AG, Chaves FL, Jacobs RE (2018). Alterations of functional circuitry in aging brain and the impact of mutated APP expression. Neurobiol Aging, 70: 276-290.
[6] Bitto A, Giuliani D, Pallio G, Irrera N, Vandini E, Canalini F, et al. (2017). Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice. Inflamm Res, 66: 389-398.
[7] Braidy N, Poljak A, Marjo C, Rutlidge H, Rich A, Jayasena T, et al. (2014). Metal and complementary molecular bioimaging in Alzheimer's disease. Front Aging Neurosci, 6: 138.
[8] Faller P, Hureau C, La Penna G (2014). Metal ions and intrinsically disordered proteins and peptides: from Cu/Zn amyloid-beta to general principles. Acc Chem Res, 47: 2252-2259.
[9] Gerber H, Wu F, Dimitrov M, Garcia Osuna GM, Fraering PC (2017). Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by gamma-Secretase and Amyloid-beta Peptide Production. J Biol Chem, 292: 3751-3767.
[10] Bush AI (2002). Metal complexing agents as therapies for Alzheimer's disease. Neurobiol Aging, 23: 1031-1038.
[11] Wang P, Wang ZY (2017). Metal ions influx is a double edged sword for the pathogenesis of Alzheimer's disease. Ageing Res Rev, 35: 265-290.
[12] Faller P, Hureau C, Berthoumieu O (2013). Role of metal ions in the self-assembly of the Alzheimer's amyloid-beta peptide. Inorg Chem, 52: 12193-12206.
[13] Ayton S, Lei P, Bush AI (2015). Biometals and their therapeutic implications in Alzheimer's disease. Neurotherapeutics, 12: 109-120.
[14] Barnham KJ, Bush AI (2014). Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem Soc Rev, 43: 6727-6749.
[15] Miller Y, Ma B, Nussinov R (2010). Zinc ions promote Alzheimer Abeta aggregation via population shift of polymorphic states. Proc Natl Acad Sci U S A, 107: 9490-9495.
[16] Wang CY, Wang T, Zheng W, Zhao BL, Danscher G, Chen YH, et al. (2010). Zinc overload enhances APP cleavage and Abeta deposition in the Alzheimer mouse brain. PLoS One, 5: e15349.
[17] Alies B, Conte-Daban A, Sayen S, Collin F, Kieffer I, Guillon E, et al. (2016). Zinc(II) Binding Site to the Amyloid-beta Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides. Inorg Chem, 55: 10499-10509.
[18] Robert A, Liu Y, Nguyen M, Meunier B (2015). Regulation of copper and iron homeostasis by metal chelators: a possible chemotherapy for Alzheimer's disease. Acc Chem Res, 48: 1332-1339.
[19] Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, et al. (2008). Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron, 59: 43-55.
[20] Jakob-Roetne R, Jacobsen H (2009). Alzheimer's disease: from pathology to therapeutic approaches. Angew Chem Int Ed Engl, 48: 3030-3059.
[21] Jiang H, Wang J, Rogers J, Xie J (2017). Brain Iron Metabolism Dysfunction in Parkinson's Disease. Mol Neurobiol, 54: 3078-3101.
[22] Guo C, Wang P, Zhong ML, Wang T, Huang XS, Li JY, et al. (2013). Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int, 62: 165-172.
[23] Wang T, Wang CY, Shan ZY, Teng WP, Wang ZY (2012). Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AbetaPP/PS1 transgenic mouse brain. J Alzheimers Dis, 29: 549-559.
[24] Matlack KE, Tardiff DF, Narayan P, Hamamichi S, Caldwell KA, Caldwell GA, et al. (2014). Clioquinol promotes the degradation of metal-dependent amyloid-beta (Abeta) oligomers to restore endocytosis and ameliorate Abeta toxicity. Proc Natl Acad Sci U S A, 111: 4013-4018.
[25] Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, et al. (2013). Functions of S100 proteins. Curr Mol Med, 13: 24-57.
[26] Lesniak W, Wilanowski T, Filipek A (2017). S100A6 - focus on recent developments. Biol Chem, 398: 1087-1094.
[27] Yamashita N, Ilg EC, Schafer BW, Heizmann CW, Kosaka T (1999). Distribution of a specific calcium-binding protein of the S100 protein family, S100A6 (calcyclin), in subpopulations of neurons and glial cells of the adult rat nervous system. J Comp Neurol, 404: 235-257.
[28] Hoyaux D, Boom A, Van den Bosch L, Belot N, Martin JJ, Heizmann CW, et al. (2002). S100A6 overexpression within astrocytes associated with impaired axons from both ALS mouse model and human patients. J Neuropathol Exp Neurol, 61: 736-744.
[29] Boom A, Pochet R, Authelet M, Pradier L, Borghgraef P, Van Leuven F, et al. (2004). Astrocytic calcium/zinc binding protein S100A6 over expression in Alzheimer's disease and in PS1/APP transgenic mice models. Biochim Biophys Acta, 1742: 161-168.
[30] Kordowska J, Stafford WF, Wang CL (1998). Ca2+ and Zn2+ bind to different sites and induce different conformational changes in human calcyclin. Eur J Biochem, 253: 57-66.
[31] Hoyaux D, Alao J, Fuchs J, Kiss R, Keller B, Heizmann CW, et al. (2000). S100A6, a calcium- and zinc-binding protein, is overexpressed in SOD1 mutant mice, a model for amyotrophic lateral sclerosis. Biochim Biophys Acta, 1498: 264-272.
[32] Deloulme JC, Assard N, Mbele GO, Mangin C, Kuwano R, Baudier J (2000). S100A6 and S100A11 are specific targets of the calcium- and zinc-binding S100B protein in vivo. J Biol Chem, 275: 35302-35310.
[33] Donato R, Sorci G, Giambanco I (2017). S100A6 protein: functional roles. Cell Mol Life Sci, 74: 2749-2760.
[34] Plonka PM, Handjiski B, Popik M, Michalczyk D, Paus R (2005). Zinc as an ambivalent but potent modulator of murine hair growth in vivo- preliminary observations. Exp Dermatol, 14: 844-853.
[35] Meeusen JW, Tomasiewicz H, Nowakowski A, Petering DH (2011). TSQ (6-methoxy-8-p-toluenesulfonamido-quinoline), a common fluorescent sensor for cellular zinc, images zinc proteins. Inorg Chem, 50: 7563-7573.
[36] Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. (2003). Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med, 9: 453-457.
[37] Zhang LH, Wang X, Zheng ZH, Ren H, Stoltenberg M, Danscher G, et al. (2008). Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain. Neurobiol Aging, 31: 74-87.
[38] Lee JY, Cho E, Seo JW, Hwang JJ, Koh JY (2012). Alteration of the cerebral zinc pool in a mouse model of Alzheimer disease. J Neuropathol Exp Neurol, 71: 211-222.
[39] Bush AI (2013). The metal theory of Alzheimer's disease. J Alzheimers Dis, 33 Suppl 1: S277-281.
[40] Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT, Atwood CS, et al. (2000). Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem, 275: 19439-19442.
[41] Damante CA, Osz K, Nagy Z, Pappalardo G, Grasso G, Impellizzeri G, et al. (2009). Metal loading capacity of Abeta N-terminus: a combined potentiometric and spectroscopic study of zinc(II) complexes with Abeta(1-16), its short or mutated peptide fragments and its polyethylene glycol-ylated analogue. Inorg Chem, 48: 10405-10415.
[42] Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP, Gusella JF, et al. (1994). Rapid induction of Alzheimer A beta amyloid formation by zinc. Science, 265: 1464-1467.
[43] Granzotto A, Sensi SL (2015). Intracellular zinc is a critical intermediate in the excitotoxic cascade. Neurobiol Dis, 81: 25-37.
[44] Inoue K, O'Bryant Z, Xiong ZG (2015). Zinc-permeable ion channels: effects on intracellular zinc dynamics and potential physiological/pathophysiological significance. Curr Med Chem, 22: 1248-1257.
[45] Hagmeyer S, Cristovao JS, Mulvihill JJE, Boeckers TM, Gomes CM, Grabrucker AM (2018). Zinc Binding to S100B Affords Regulation of Trace Metal Homeostasis and Excitotoxicity in the Brain. Front Mol Neurosci, 10: 456.
[46] Cristovao JS, Santos R, Gomes CM (2016). Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer's Disease. Oxid Med Cell Longev, 2016:9812178.
[47] Tsoporis JT, Izhar S, Desjardins JF, Leong-Poi H, Parker TG (2014). Conditional cardiac overexpression of S100A6 attenuates myocyte hypertrophy and apoptosis following myocardial infarction. Curr Pharm Des, 20: 1941-1949.
[48] Mofid A, Newman NS, Lee PJ, Abbasi C, Matkar PN, Rudenko D, et al. (2017). Cardiac Overexpression of S100A6 Attenuates Cardiomyocyte Apoptosis and Reduces Infarct Size After Myocardial Ischemia-Reperfusion. J Am Heart Assoc, 6.
[49] Fang B, Liang M, Yang G, Ye Y, Xu H, He X, et al. (2014). Expression of S100A6 in rat hippocampus after traumatic brain injury due to lateral head acceleration. Int J Mol Sci, 15: 6378-6390.
[50] Courtois-Coutry N, Le Moellic C, Boulkroun S, Fay M, Cluzeaud F, Escoubet B, et al. (2002). Calcyclin is an early vasopressin-induced gene in the renal collecting duct. Role in the long term regulation of ion transport. J Biol Chem, 277: 25728-25734.
[51] Hong EJ, Park SH, Choi KC, Leung PC, Jeung EB (2006). Identification of estrogen-regulated genes by microarray analysis of the uterus of immature rats exposed to endocrine disrupting chemicals. Reprod Biol Endocrinol, 4: 49.
[52] Lesniak W, Szczepanska A, Kuznicki J (2005). Calcyclin (S100A6) expression is stimulated by agents evoking oxidative stress via the antioxidant response element. Biochim Biophys Acta, 1744: 29-37.
[53] Orre LM, Pernemalm M, Lengqvist J, Lewensohn R, Lehtio J (2007). Up-regulation, modification, and translocation of S100A6 induced by exposure to ionizing radiation revealed by proteomics profiling. Mol Cell Proteomics, 6: 2122-2131.
[54] Tsoporis JN, Izhar S, Parker TG (2008). Expression of S100A6 in cardiac myocytes limits apoptosis induced by tumor necrosis factor-alpha. J Biol Chem, 283: 30174-30183.
[55] Tu Q, Pi M, Quarles LD (2003). Calcyclin mediates serum response element (SRE) activation by an osteoblastic extracellular cation-sensing mechanism. J Bone Miner Res, 18: 1825-1833.
[56] Bozym RA, Chimienti F, Giblin LJ, Gross GW, Korichneva I, Li Y, et al. (2010). Free zinc ions outside a narrow concentration range are toxic to a variety of cells in vitro. Exp Biol Med (Maywood), 235: 741-750.
[1] Yamanaka Takehiko, Uchida Yuto, Sakurai Keita, Kato Daisuke, Mizuno Masayuki, Sato Toyohiro, Madokoro Yuta, Kondo Yuko, Suzuki Ayuko, Ueki Yoshino, Ishii Fumiyasu, Borlongan Cesar V, Matsukawa Noriyuki. Anatomical Links between White Matter Hyperintensity and Medial Temporal Atrophy Reveal Impairment of Executive Functions[J]. Aging and disease, 2019, 10(4): 711-718.
[2] Li Yu-Sheng, Yang Zhi-Hua, Zhang Yao, Yang Jing, Shang Dan-Dan, Zhang Shu-Yu, Wu Jun, Ji Yan, Zhao Lu, Shi Chang-He, Xu Yu-Ming. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease[J]. Aging and disease, 2019, 10(4): 908-914.
[3] Tao Qing-Qing, Chen Yu-Chao, Wu Zhi-Ying. The role of CD2AP in the Pathogenesis of Alzheimer's Disease[J]. Aging and disease, 2019, 10(4): 901-907.
[4] Li Kunyu, Li Jiatong, Zheng Jialin, Qin Song. Reactive Astrocytes in Neurodegenerative Diseases[J]. Aging and disease, 2019, 10(3): 664-675.
[5] Cho Kyoungjoo. Emerging Roles of Complement Protein C1q in Neurodegeneration[J]. Aging and disease, 2019, 10(3): 652-663.
[6] Bi Christopher, Bi Stephanie, Li Bin. Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 383-403.
[7] Jeon Seong Gak, Song Eun Ji, Lee Dongje, Park Junyong, Nam Yunkwon, Kim Jin-il, Moon Minho. Traditional Oriental Medicines and Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 307-328.
[8] Shetty Ashok K., Upadhya Raghavendra, Madhu Leelavathi N., Kodali Maheedhar. Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 470-482.
[9] Jong Bin Bae,Ji Won Han,Kyung Phil Kwak,Bong Jo Kim,Shin Gyeom Kim,Jeong Lan Kim,Tae Hui Kim,Seung-Ho Ryu,Seok Woo Moon,Joon Hyuk Park,Jong Chul Youn,Dong Young Lee,Dong Woo Lee,Seok Bum Lee,Jung Jae Lee,Jin Hyeong Jhoo,Ki Woong Kim. Is Dementia More Fatal Than Previously Estimated? A Population-based Prospective Cohort Study[J]. Aging and disease, 2019, 10(1): 1-11.
[10] Antonina Luca, Carmela Calandra, Maria Luca. Molecular Bases of Alzheimer’s Disease and Neurodegeneration: The Role of Neuroglia[J]. Aging and disease, 2018, 9(6): 1134-1152.
[11] Sone Daichi, Imabayashi Etsuko, Maikusa Norihide, Ogawa Masayo, Sato Noriko, Matsuda Hiroshi, Japanese-Alzheimer’s Disease Neuroimaging Initiative. Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on 3-tesla Normal Database: Diagnostic Accuracy in Two Independent Cohorts with Early Alzheimer’s Disease[J]. Aging and disease, 2018, 9(4): 755-760.
[12] Morroni Fabiana, Sita Giulia, Graziosi Agnese, Turrini Eleonora, Fimognari Carmela, Tarozzi Andrea, Hrelia Patrizia. Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway[J]. Aging and disease, 2018, 9(4): 605-622.
[13] Li Wenjun, Roy Choudhury Gourav, Winters Ali, Prah Jude, Lin Wenping, Liu Ran, Yang Shao-Hua. Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation[J]. Aging and disease, 2018, 9(4): 674-684.
[14] Xu Yangqi, Liu Xiaoli, Shen Junyi, Tian Wotu, Fang Rong, Li Binyin, Ma Jianfang, Cao Li, Chen Shengdi, Li Guanjun, Tang Huidong. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia[J]. Aging and disease, 2018, 9(4): 696-705.
[15] Ding Qiong, Tanigawa Kitora, Kaneko Jun, Totsuka Mamoru, Katakura Yoshinori, Imabayashi Etsuko, Matsuda Hiroshi, Hisatsune Tatsuhiro. Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4[J]. Aging and disease, 2018, 9(3): 334-345.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd