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Phosphorylation of ULK1 \(hATG1\) by AMP-activated protein \ kinase connects energy sensing to mitophagy. 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Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and\ NAD+ /SIRT1 reduction. Cell 157, 882 896 \(2014\).\r:2537)/F 4/H/N/Rect[227.76 601.206 232.965 588.66]/Subtype/Link/Type/Annot>> endobj 37 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 14. Toyama, E. Q. et al. Metabolism. AMP-activated protein kinase \nmediates mitoc\ hondrial fission in response to energy stress. Science 351, 275 281 \(2016\).\r:2538)/F 4/H/N/Rect[234.201 601.206 239.406 588.66]/Subtype/Link/Type/Annot>> endobj 38 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 15. Egan, D. F. et al. Phosphorylation of ULK1 \(hATG1\) by AMP-activated protein\ kinase connects energy sensing to mitophagy. Science 331, \n456 461 \(2011\).\r:2539)/F 4/H/N/Rect[240.642 601.206 245.847 588.66]/Subtype/Link/Type/Annot>> endobj 39 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 2. Kerr, J. S. et al. Mitophagy and Alzheimer s disease: cellular and molecu\ lar mechanisms. Trends Neurosci. 40, 151 166 \(2017\).\r:2540)/F 4/H/N/Rect[82.5651 569.706 85.1676 557.16]/Subtype/Link/Type/Annot>> endobj 40 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 16. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to \ induce mitophagy. Nature 524, 309 314 \(2015\).\r:2541)/F 4/H/N/Rect[286.433 548.706 291.638 536.16]/Subtype/Link/Type/Annot>> endobj 41 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 15. Egan, D. F. et al. Phosphorylation of ULK1 \(hATG1\) by AMP-activated protei\ n kinase connects energy sensing to mitophagy. Science 331, \n456 461 \(2011\).\r:2542)/F 4/H/N/Rect[126.677 538.206 131.882 525.66]/Subtype/Link/Type/Annot>> endobj 42 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 1 | Mitochondrial dysfunction and defective mitophagy in human patient brai\ n samples and AD patient iPSC-derived cultured neurons. \na, Quantification of mitochondrial parameters from electron micr\ oscopy images in postmortem human h:2543)/F 4/H/N/Rect[81.3192 527.706 88.5359 515.16]/Subtype/Link/Type/Annot>> endobj 43 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 17. Handel, A. E. et al. Assessing similarity to primary tissue and cortical layer\ identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics. Hum. Mol. 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Mitophagy and Alzheimer s disease: cellular and mole\ cular mechanisms. Trends Neurosci. 40, 151 166 \(2017\).\r:2556)/F 4/H/N/Rect[444.784 706.206 447.408 693.66]/Subtype/Link/Type/Annot>> endobj 56 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 11. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation a\ nd NAD+ /SIRT1 reduction. Cell 157, 882 896 \(2014\).\r:2557)/F 4/H/N/Rect[448.666 706.206 453.914 693.66]/Subtype/Link/Type/Annot>> endobj 57 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 12. Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan in a\ taxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566 581 \(2016\).\r:2558)/F 4/H/N/Rect[455.172 706.206 460.42 693.66]/Subtype/Link/Type/Annot>> endobj 58 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 21. Fivenson, E. M. et al. Mitophagy in neurodegeneration and aging. Neurochem. I\ nt. 109, 202 209 \(2017\).\r:2559)/F 4/H/N/Rect[461.678 706.206 466.926 693.66]/Subtype/Link/Type/Annot>> endobj 59 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 22. Zhang, J. H., Chung, T. D. & Oldenburg, K. R. A simple statistical parameter f\ or use in evaluation and validation of high throughput screening assays. \nJ. Biomol. Screen. 4, 67 73 \(1999\).\r:2560)/F 4/H/N/Rect[455.124 643.327 460.372 630.66]/Subtype/Link/Type/Annot>> endobj 60 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 10. Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy \nand \ mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525 528 \(2015\).\r:2561)/F 4/H/N/Rect[484.719 632.706 489.967 620.16]/Subtype/Link/Type/Annot>> endobj 61 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 23. Fang, E. F. et al. In vitro and in vivo detection of mitophagy in human cells, C\ . elegans, and mice. J. Vis. Exp. https://doi.org/10.3791/56301 \(2017\).\r:2562)/F 4/H/N/Rect[491.225 632.706 496.473 620.16]/Subtype/Link/Type/Annot>> endobj 62 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 12. Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan in \ ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566 581 \(2016\).\r:2563)/F 4/H/N/Rect[525.869 527.706 531.117 515.16]/Subtype/Link/Type/Annot>> endobj 63 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 21. Fivenson, E. M. et al. Mitophagy in neurodegeneration and aging. Neurochem. \ Int. 109, 202 209 \(2017\).\r:2564)/F 4/H/N/Rect[532.375 527.706 537.623 515.16]/Subtype/Link/Type/Annot>> endobj 64 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 24. Aman, Y., Qiu, Y., Tao, J. & Fang, E. F. Therapeutic potential of boosting NAD\ + in aging and age-related diseases. Transl. Med. 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Fatouros, C. et al. Inhibition of tau aggregation in a novel Caenorhabditis e\ legans model of tauopathy mitigates proteotoxicity. Hum. Mol. Genet. 21, 3587 3603 \(2012\).\r:2574)/F 4/H/N/Rect[128.936 685.328 134.141 672.661]/Subtype/Link/Type/Annot>> endobj 81 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 29. Lublin, A. L. & Link, C. D. Alzheimer s disease drug discovery: in vivo screen\ ing using C. elegans as a model for  -amyloid peptide-induced toxicity. Drug Discov. Today Technol. 10, e115 e119 \(2013\)\ .\r:2575)/F 4/H/N/Rect[135.378 685.328 140.582 672.661]/Subtype/Link/Type/Annot>> endobj 82 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 2 | Mitophagy induction restores memory in A1 42 C. elegans model of\ AD. a, Transgenic animals expressing the mtRosella biosensor in neuronal cells were treated with NMN, UA, and AC. 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"c-*@*ƁJH[BK|syGٍ8h chcINٍl8[(}/:Jr%{t _['}";6<%W%V''tApx%2T(?Tg>?Tg MosD}9nxtDHI67Fm~ߐS#_]`bl._T:׻F/\#Yuw;5 Q뫔f5(ԇ⟕uд.d i=)P1 =u_'> uM9<h%۟@P"GŅ+2 iBuƱIVXC"lݠ!]Bj2& V83ʔPKIy h%1s=ux\M4Ρ4PIZ英َw9/ 5,ի]Ʒ.Lu`-gzZ7ȏhIn%9gKa,bm-"& {_c-k胼#DR$oB=Pi}QŌnl0 Z(yEyZEPGC=:OGauğZZ\ſEOoڡPm,Xj'֠e`>;fI,ҚJPA@) ^0Gg|gZbU6P I{e  UX_}*I2Gt|z i{I LLњ'\n-(H hݵSࡕ.e$:qF LlDvVփXE,@)FǭAei.HK*7F[-!k7Å2}Bi"ݧ 4oL|v/[i_S/&PM2㧹 ƮWs,g8)j q9vfa[<PDInlVXj UsHHr}j5֧t}gbb\Bޖ'kmX'0xcTZ ;[I$ )#\85J icqԄjb]î 5 mPEGvO_؛cP W^ °Y"&qWH1ߩ!ἕd}:Me=ݫ[)[HBJE ( $S̓Ȉ C)D,!6;[uAo Տn{#OV >qdW5ռp\]Š'gg ?krwANz>#F&-(* m(  Uillj>LVϙ֑Bs6zcs6z`5AkLW(>sg(lJ-nMuBGσ>}NW$HqDj$,nlLT)%cδTA#Hy;"h B$-)b B)Tkv^#BB*`"Fe"5Vod>{'}:wn endstream endobj 135 0 obj <> endobj 136 0 obj [137 0 R 138 0 R 139 0 R 140 0 R] endobj 137 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 3 | Mitophagy induction ameliorates A pathology and cognitive decline in\ APP/PS1 AD mice. 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APP/PS1 mice were treated with UA \(200 mg kg day"1\) or AC \(30 mg kg day"1\) by daily gavage for 2 mo\ nths starting from 6 months of age; :2592)/F 4/H/N/Rect[117.811 716.707 126.887 704.161]/Subtype/Link/Type/Annot>> endobj 164 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 32. Selkoe, D. J. Alzheimer s disease is a synaptic failure. Science 298, \n789\ 791 \(2002\).\r:2593)/F 4/H/N/Rect[152.112 674.707 157.317 662.161]/Subtype/Link/Type/Annot>> endobj 165 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load \ and modifies microglia. Nature 540, 230 235 \(2016\).\r:2594)/F 4/H/N/Rect[284.312 601.207 289.517 588.661]/Subtype/Link/Type/Annot>> endobj 166 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load\ and modifies microglia. Nature 540, 230 235 \(2016\).\r:2595)/F 4/H/N/Rect[86.0244 485.707 91.2293 473.161]/Subtype/Link/Type/Annot>> endobj 167 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 33. Keren-Shaul, H. et al. A unique microglia type associated with \nrestricting de\ velopment of Alzheimer s disease. Cell 169, \n1276 1290.e17 \(2017\).\r:2596)/F 4/H/N/Rect[92.4655 485.707 97.6704 473.161]/Subtype/Link/Type/Annot>> endobj 168 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and inhibits\ neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A plaques\ . A plaques are shown in green \(:2597)/F 4/H/N/Rect[204.418 443.707 212.964 431.161]/Subtype/Link/Type/Annot>> endobj 169 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid loa\ d and modifies microglia. Nature 540, 230 235 \(2016\).\r:2598)/F 4/H/N/Rect[156.391 391.207 161.596 378.661]/Subtype/Link/Type/Annot>> endobj 170 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and inhibit\ s neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A plaque\ s. A plaques are shown in green :2599)/F 4/H/N/Rect[202.628 328.207 211.816 315.661]/Subtype/Link/Type/Annot>> endobj 171 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and inhibi\ ts neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A plaqu\ es. A plaques are shown in green:2600)/F 4/H/N/Rect[539.02 727.207 547.418 714.661]/Subtype/Link/Type/Annot>> endobj 172 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and inhib\ its neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A plaq\ ues. A plaques are shown in gree:2601)/F 4/H/N/Rect[366.859 706.207 376.234 693.661]/Subtype/Link/Type/Annot>> endobj 173 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and inhi\ bits neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A pla\ ques. A plaques are shown in gre:2602)/F 4/H/N/Rect[323.712 685.207 339.14 672.661]/Subtype/Link/Type/Annot>> endobj 174 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid lo\ ad and modifies microglia. Nature 540, 230 235 \(2016\).\r:2603)/F 4/H/N/Rect[409.052 611.707 414.257 599.161]/Subtype/Link/Type/Annot>> endobj 175 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 33. Keren-Shaul, H. et al. A unique microglia type associated with \nrestricting d\ evelopment of Alzheimer s disease. Cell 169, \n1276 1290.e17 \(2017\).\r:2604)/F 4/H/N/Rect[415.493 611.707 420.698 599.161]/Subtype/Link/Type/Annot>> endobj 176 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 34. Babcock, A. A. et al. Cytokine-producing microglia have an altered beta-amyloi\ d load in aged APP/PS1 Tg mice. Brain Behav. Immun. 48, 86 101 \(2015\).\r:2605)/F 4/H/N/Rect[545.431 601.207 550.636 588.661]/Subtype/Link/Type/Annot>> endobj 177 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and inh\ ibits neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A pl\ aques. A plaques are shown in gr:2606)/F 4/H/N/Rect[386.66 549.321 400.619 535.278]/Subtype/Link/Type/Annot>> endobj 178 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 35. Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-infl\ ammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513 519 \(2017\).\r:2607)/F 4/H/N/Rect[329.064 527.707 334.269 515.161]/Subtype/Link/Type/Annot>> endobj 179 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and in\ hibits neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A p\ laques. A plaques are shown in g:2608)/F 4/H/N/Rect[428.917 517.207 437.734 504.661]/Subtype/Link/Type/Annot>> endobj 180 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and i\ nhibits neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A \ plaques. A plaques are shown in :2609)/F 4/H/N/Rect[439.585 422.707 453.628 410.161]/Subtype/Link/Type/Annot>> endobj 181 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 36. Heneka, M. T. et al. NLRP3 is activated in Alzheimer s disease \nand contribute\ s to pathology in APP/PS1 mice. Nature 493, \n674 678 \(2013\).\r:2610)/F 4/H/N/Rect[545.431 380.707 550.636 368.161]/Subtype/Link/Type/Annot>> endobj 182 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 2 | Mitophagy induction restores memory in A1 42 C. elegans mode\ l of AD. a, Transgenic animals expressing the mtRosella biosensor in neuronal cells were treated with NMN, UA, and AC. Rel\ ative levels of neuronal mitophagy:2622)/F 4/H/N/Rect[158.715 203.276 167.011 192.932]/Subtype/Link/Type/Annot>> endobj 183 0 obj <>/BS<>/Border[0 0 0]/F 4/H/N/Rect[446.803 33.864 552.756 25.1497]/Subtype/Link/Type/Annot>> endobj 184 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 185 0 obj <>stream x]YoWv3Y`j_4eHaXAP.fw[`~A0/ YZKZL!DvWݺsď'O ɳU nN~}ɓsp= o;[ˮ D(oN Oۓҏ/oIae(Ӡ,׫ウIy/Iyfn2$,d% zIf{S([_`fO(˂l~ ܏ Gϒ2Dp'&!\AeI{5L՛w0igs/d:f{?M^Pp&y읊jRºo. b9!v2-Z^FCk<(oJbNآ IlPwi)iu,b-HV zRxb#XAĠoqDoB F04v`T3XiS!=Z*sݾc Xo*`F}ЧA!<1訁Vs}@j1@b{ |#K=aq@py6.K t^u/s`G1FZ2W'6ijͩ,|k%?HRi7VeQ$/)SdAQSfRO⸝:legyQ fSjض_^m;&y7C KzvilcEl=Rre :W 闥.AR#Ltdzkf&%;t\`H=nhXֱd 9:#@>j Y,,p?9VlHs/hu;ڒyoꨈKP1[2:{[?J-Ckađ N sg,2K4!#v33\{_kt5,CU`-vzI0`NMi1;l ۞`qIX] L+i4 VȦ2\8xclBgVmt3![hZdnlS+4=]x? 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Lw Sts닔߫aRYfދfgݢŢ|?5. lԮڋJ.,wwb߿[VbدXsX_YWKؑr+5p-Kw+:-y:}Q/jmͼ^Еշ:˾%[tüS`q\&fyTPrwu*q3j7?am ܈).L )\fp5r;)Aeݡ^UFVA.;w,zYߊ"<!]ė(S+z=s^vZEXQƭU8Z,ÛE43/y \-D iSG1Մġ!_\-Cw&xgXn@`mo0^ CEE o?ֻ`}^ = n$a໬d;h| ~Ʈ_$0cp*7Wx֮ډ> ,}\i*0k_~} PD_gU&dyOtVQE5ki =¼Wd'IDgy=k&.kky=8qL*ճn1Y'o:a@Po/i)/j;~B]-epkU 3ۂt!~Rr|g~$AK5ʷT%ۛtbrkq}g@lMjEڭ{Qa;zMmM{,x+}VTI,ku+8E."Wd^}{/ր8ӓ؟9p\۝ w;}?-(^%:jho2A-1ovq[(u --}&.N%[lSLi2f]O8io'eqfX@]?ߴ1d~[uo]hΎ4fȘH1kp< HFϜ'``̋Z-xoI[ߢjS4m-½Y@M^-U3e,Z1Κ"! /S#D\A\լ$b?r"k; ÀjG@zޒfV-+E /Db-eD9|~=I?g/5VՊ6ﰂ[>G-/% R*-x@'_]z7%Y` O"wۣuDMrx0(.[lx@c͠3k.d 2â`i)ѓIW-[!XZ {18@ mPk3c>[ԫͮ3I.+T==RZsAȧb{Ŧہi8XW%ͽcpimEaLCD 3&IDu |jSIs?y?qQR ^LXɋYeTг$F]CG= 8e;G }µٙCHT,$4O8ʤˍT?E{;,s.aP0wzķ{c| N܍  ]ˆjTIIQ!>bS>Xu${ /uqL{ p7z' 1UOdXSB ›+^T+ۜye jg ȕv :#JrTv]3rgqUV AR* |)sY?L]}ʗ>z}y1ǻR`BY4"L(ICQF~à1VouM[B@UӸqҴ(\B @Euae^5wvyv(lJ1ǴM@"niluS=haj=U L5zw,\w"w=v-]cU^ܘ)h{3Gs|"2Թx>3jB]S;X Uw?f}G0yي֐5k6",kNA# 56OmƾE+=.fv)rJe|@To{8 ]ItۆQ ƦRswU@b`K [li1x,2xd+'T)3SA-bqe=9Q”f =sd3 lFW nN:vN(Za> ݚ_oɓ@_[=IċOB4iR?'ǾϢ(ݺ:AeJoO'W'F("X>';`)K©s5'(47ջ¦2)&5<.N\vN29)@8&3|Zi:[-> endobj 187 0 obj [188 0 R 189 0 R 190 0 R 191 0 R 192 0 R 193 0 R 194 0 R 195 0 R 196 0 R 197 0 R 198 0 R 199 0 R] endobj 188 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 4 | Mitophagy induction promotes phagocytic activity of microglia and \ inhibits neuronal inflammation in APP/PS1 AD mice. a, Representative images showing microglial cells engulfing or near A \ plaques. A plaques are shown in:2611)/F 4/H/N/Rect[219.119 738.321 225.964 724.278]/Subtype/Link/Type/Annot>> endobj 189 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 6. Mairet-Coello, G. et al. The CAMKK2-AMPK kinase pathway mediates the synaptoto\ xic effects of A oligomers through Tau phosphorylation. Neuron 78, 94 108 \(2013\).\r:2612)/F 4/H/N/Rect[115.559 590.707 118.161 578.161]/Subtype/Link/Type/Annot>> endobj 190 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 37. Spillantini, M. G. & Goedert, M. Tau pathology and neurodegeneration. Lancet \ Neurol. 12, 609 622 \(2013\).\r:2613)/F 4/H/N/Rect[119.397 590.707 124.602 578.161]/Subtype/Link/Type/Annot>> endobj 191 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 37. Spillantini, M. G. & Goedert, M. Tau pathology and neurodegeneration. Lancet\ Neurol. 12, 609 622 \(2013\).\r:2614)/F 4/H/N/Rect[169.501 569.707 174.706 557.161]/Subtype/Link/Type/Annot>> endobj 192 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 38. Hanger, D. P. et al. Novel phosphorylation sites in tau from Alzheimer brain s\ upport a role for casein kinase 1 in disease pathogenesis. J. Biol. Chem. 282, 23645 23654 \(2007\).\r:2615)/F 4/H/N/Rect[175.942 569.707 181.147 557.161]/Subtype/Link/Type/Annot>> endobj 193 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 5 | Mitophagy induction inhibits tau hyperphosphorylation in human neuronal ce\ lls and enhances memory in a tau C. elegans model and a 3TgAD mouse model. a, Levels of p-tau in human SH-SY5Y neurobla\ stoma cells overexpressing 2N4R, 1:2616)/F 4/H/N/Rect[526.609 727.207 535.155 714.661]/Subtype/Link/Type/Annot>> endobj 194 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd:Fig. 5 | Mitophagy induction inhibits tau hyperphosphorylation in human neuronal c\ ells and enhances memory in a tau C. elegans model and a 3TgAD mouse model. a, Levels of p-tau in human SH-SY5Y neurobl\ astoma cells overexpressing 2N4R, :2617)/F 4/H/N/Rect[414.943 695.707 424.131 683.161]/Subtype/Link/Type/Annot>> endobj 195 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 28. Fatouros, C. et al. Inhibition of tau aggregation in a novel Caenorhabditis \ elegans model of tauopathy mitigates proteotoxicity. Hum. Mol. 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Mazure, C. M. & Swendsen, J. Sex differences in Alzheimer s \ndisease and other\ dementias. Lancet Neurol. 15, \n451 452 \(2016\).\r:2627)/F 4/H/N/Rect[110.414 548.707 115.619 536.161]/Subtype/Link/Type/Annot>> endobj 224 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 2. Kerr, J. S. et al. Mitophagy and Alzheimer s disease: cellular and m\ olecular mechanisms. Trends Neurosci. 40, 151 166 \(2017\).\r:2628)/F 4/H/N/Rect[130.41 380.707 133.012 368.161]/Subtype/Link/Type/Annot>> endobj 225 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 41. Swerdlow, R. H., Burns, J. M. & Khan, S. M. The Alzheimer s disease mitochondr\ ial cascade hypothesis: progress and perspectives. Biochim. Biophys. Acta 1842, 1219 1231 \(2014\).\r:2629)/F 4/H/N/Rect[134.248 380.707 139.453 368.161]/Subtype/Link/Type/Annot>> endobj 226 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 4. Sorrentino, V. et al. Enhancing mitochondrial proteostasis reduces amyloid- \ proteotoxicity. Nature 552, 187 193 \(2017\).\r:2630)/F 4/H/N/Rect[223.673 359.707 226.275 347.161]/Subtype/Link/Type/Annot>> endobj 227 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 42. Martn-Maestro, P. et al. Mitophagy failure in fibroblasts and iPSC-derived ne\ urons of Alzheimer s disease-associated presenilin 1 mutation. Front. Mol. Neurosci. 10, 291 \(2017\).\r:2631)/F 4/H/N/Rect[277.871 349.207 283.076 336.661]/Subtype/Link/Type/Annot>> endobj 228 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 43. Ye, X., Sun, X., Starovoytov, V. & Cai, Q. Parkin-mediated mitophagy in mutant\ hAPP neurons and Alzheimer s disease patient brains. Hum. Mol. Genet. 24, 2938 2951 \(2015\).\r:2632)/F 4/H/N/Rect[284.312 349.207 289.517 336.661]/Subtype/Link/Type/Annot>> endobj 229 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 14. Toyama, E. Q. et al. Metabolism. 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Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71 94 \(\ 1974\).\r:2658)/F 4/H/N/Rect[256.942 727.549 261.139 717.109]/Subtype/Link/Type/Annot>> endobj 277 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 52. Samara, C., Syntichaki, P. & Tavernarakis, N. Autophagy is required for necrot\ ic cell death in Caenorhabditis elegans. Cell Death Differ. 15, \n105 112 \(2008\).\r:2659)/F 4/H/N/Rect[262.136 727.549 266.334 717.109]/Subtype/Link/Type/Annot>> endobj 278 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 10. Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy \nan\ d mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525 528 \(2015\).\r:2660)/F 4/H/N/Rect[191.11 378.103 195.194 367.888]/Subtype/Link/Type/Annot>> endobj 279 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 10. Palikaras, K., Lionaki, E. & Tavernarakis, N. 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Ghosal, K. et al. Alzheimer s disease-like pathological features in transgenic\ mice expressing the APP intracellular domain. Proc. Natl Acad. Sci. USA 106, 18367 18372 \(2009\).\r:2679)/F 4/H/N/Rect[190.484 659.922 194.682 648.597]/Subtype/Link/Type/Annot>> endobj 309 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid \ load and modifies microglia. Nature 540, 230 235 \(2016\).\r:2680)/F 4/H/N/Rect[90.7738 624.627 94.9714 614.509]/Subtype/Link/Type/Annot>> endobj 310 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 39. Hou, Y. et al. NAD+ supplementation normalizes key Alzheimer s features and\ DNA damage responses in a new AD mouse model with \nintroduced DNA repair deficiency. Proc. Natl Acad. Sci. 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NAD+ supplementation normalizes key Alzheimer s features a\ nd DNA damage responses in a new AD mouse model with \nintroduced DNA repair deficiency. Proc. Natl Acad. Sci. USA 115, E187\ 6 E1885 \(2018\).\r:2684)/F 4/H/N/Rect[147.23 388.505 151.427 378.388]/Subtype/Link/Type/Annot>> endobj 314 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 58. Scheibye-Knudsen, M. et al. A high-fat diet and NAD+ activate Sirt1 to rescu\ e premature aging in cockayne syndrome. Cell Metab. 20, 840 855 \(2014\).\r:2685)/F 4/H/N/Rect[142.553 220.763 146.75 210.645]/Subtype/Link/Type/Annot>> endobj 315 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloi\ d load and modifies microglia. Nature 540, 230 235 \(2016\).\r:2686)/F 4/H/N/Rect[486.176 729.522 490.373 718.197]/Subtype/Link/Type/Annot>> endobj 316 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 11. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation\ and NAD+ /SIRT1 reduction. Cell 157, 882 896 \(2014\).\r:2687)/F 4/H/N/Rect[494.757 619.153 499.068 609.036]/Subtype/Link/Type/Annot>> endobj 317 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 12. Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan \ in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566 581 \(2016\).\r:2688)/F 4/H/N/Rect[500.122 619.153 504.433 609.036]/Subtype/Link/Type/Annot>> endobj 318 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 11. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivatio\ n and NAD+ /SIRT1 reduction. Cell 157, 882 896 \(2014\).\r:2689)/F 4/H/N/Rect[341.482 62.3534 345.793 52.2359]/Subtype/Link/Type/Annot>> endobj 319 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 12. Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan\ in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566 581 \(2016\).\r:2690)/F 4/H/N/Rect[346.847 62.3534 351.158 52.2359]/Subtype/Link/Type/Annot>> endobj 320 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 16. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors t\ o induce mitophagy. Nature 524, 309 314 \(2015\).\r:2691)/F 4/H/N/Rect[352.212 62.3534 356.523 52.2359]/Subtype/Link/Type/Annot>> endobj 321 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 30. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amylo\ id load and modifies microglia. 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Hou, Y. et al. Smart Soup, a traditional Chinese medicine formula, ameliorates\ amyloid pathology and related cognitive deficits. PLoS One 9, e111215 \(2014\).\r:2693)/F 4/H/N/Rect[137.303 720.822 141.5 709.497]/Subtype/Link/Type/Annot>> endobj 328 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 60. Koopman, M. et al. A screening-based platform for the assessment of cellular r\ espiration in Caenorhabditis elegans. Nat. Protoc. 11, 1798 1816 \(2016\).\r:2694)/F 4/H/N/Rect[239.473 398.427 243.671 388.309]/Subtype/Link/Type/Annot>> endobj 329 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 61. Fang, E. F. et al. Tomatidine enhances lifespan and healthspan in C. elegans\ through mitophagy induction via the SKN-1/Nrf2 pathway. Sci. Rep. 7, \n46208 \(2017\).\r:2695)/F 4/H/N/Rect[244.668 398.427 248.865 388.309]/Subtype/Link/Type/Annot>> endobj 330 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 11. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivati\ on and NAD+ /SIRT1 reduction. Cell 157, 882 896 \(2014\).\r:2696)/F 4/H/N/Rect[151.395 259.227 155.593 249.109]/Subtype/Link/Type/Annot>> endobj 331 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 62. Brewer, G. J. & Torricelli, J. R. Isolation and culture of adult neurons and n\ eurospheres. Nat. Protoc. 2, 1490 1498 \(2007\).\r:2697)/F 4/H/N/Rect[156.59 259.227 160.787 249.109]/Subtype/Link/Type/Annot>> endobj 332 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 63. Forester, C. M. et al. Revealing nascent proteomics in signaling pathways and \ cell differentiation. Proc. Natl Acad. Sci. USA 115, 2353 2358 \(2018\).\r:2698)/F 4/H/N/Rect[66.5117 189.627 70.7093 179.509]/Subtype/Link/Type/Annot>> endobj 333 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatNeuro_332.indd: 64. Skamagki, M. et al. ZSCAN10 expression corrects the genomic instability of iPS\ Cs from aged donors. Nat. 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Fang Yujun Hou Konstantinos Palikaras Bryan A. Adriaanse Jesse S. Kerr Beimeng Yang Sofie Lautrup Md Mahdi Hasan-Olive Domenica Caponio Xiuli Dan Paula Rocktäschel Deborah L. Croteau Mansour Akbari Nigel H. Greig Tormod Fladby Hilde Nilsen M. Zameel Cader Mark P. Mattson Nektarios Tavernarakis Vilhelm A. Bohr 10.1038/s41593-018-0332-9 http://dx.doi.org/10.1038/s41593-018-0332-9 journal Nature Neuroscience © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. 1546-1726 10.1038/s41593-018-0332-9 springer.com springerlink.com 2010-04-23 True 10.1038/s41593-018-0332-9 springer.com springerlink.com Springer 2020-02-06T15:46:52-06:00 2019-02-15T13:38:21+05:30 2020-02-06T15:46:52-06:00 True VoR uuid:24102e69-41ed-4929-bac1-7fc7d5a9885a uuid:d48dda34-00a5-456c-8ed9-e79849b08322 default 1 converted uuid:553e2dda-df77-4c9c-8100-3c48ccb10e91 converted to PDF/A-2b pdfToolbox 2019-02-15T13:39:13+05:30 2 B Evandro F. 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