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Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model

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Abstract

TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.

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References

  1. Alfieri JA, Pino NS, Igaz LM (2014) reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies. J Neurosci 34:15244–15259. doi:10.1523/JNEUROSCI.1918-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia 12(4):459–509

    Article  Google Scholar 

  3. Amador-Ortiz C, Lin W-L, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. doi:10.1002/ana.21154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Andrade-Moraes CH, Oliveira-Pinto AV, Castro-Fonseca E, da Silva CG, Guimarães DM, Szczupak D, Parente-Bruno DR, Carvalho LRB, Polichiso L, Gomes BV, Oliveira LM, Rodriguez RD, Leite REP, Ferretti-Rebustini REL, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Lent R (2013) Cell number changes in Alzheimer’s disease relate to dementia, not to plaques and tangles. Brain 136:3738–3752. doi:10.1093/brain/awt273

    Article  PubMed  PubMed Central  Google Scholar 

  5. Beach TG, Monsell SE, Phillips LE, Kukull W (2012) Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropathol Exp Neurol 71:266–273. doi:10.1097/NEN.0b013e31824b211b

    Article  PubMed  PubMed Central  Google Scholar 

  6. Burgess BL, McIsaac SA, Naus KE, Chan JY, Tansley GHK, Yang J, Miao F, Ross CJD, van Eck M, Hayden MR, van Nostrand W, St George-Hyslop P, Westaway D, Wellington CL (2006) Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant A beta in plasma. Neurobiol Dis 24:114–127. doi:10.1016/j.nbd.2006.06.007

    Article  CAS  PubMed  Google Scholar 

  7. Calhoun ME, Jucker M, Martin LJ, Thinakaran G, Price DL, Mouton PR (1996) Comparative evaluation of synaptophysin-based methods for quantification of synapses. J Neurocytol 25:821–828. doi:10.1007/BF02284844

    Article  CAS  PubMed  Google Scholar 

  8. Chen D, Fan W, Lu Y, Ding X, Chen S, Zhong Q (2012) A Mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Mol Cell 45:629–641. doi:10.1016/j.molcel.2011.12.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chiang P-M, Ling J, Jeong YH, Price DL, Aja SM, Wong PC (2010) Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci 107:16320–16324. doi:10.1073/pnas.1002176107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. D’Amelio M, Cavallucci V, Cecconi F (2010) Neuronal caspase-3 signaling: not only cell death. Cell Death Differ 17:1104–1114. doi:10.1038/cdd.2009.180

    Article  CAS  PubMed  Google Scholar 

  11. Davis D, Schmitt F, Wekstein D, Markesbery W (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388

    Article  CAS  PubMed  Google Scholar 

  12. Fernandez-Martos CM, King AE, Atkinson RAK, Woodhouse A, Vickers JC (2015) Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite and synaptic pathology in the APP/PS1 transgenic model of Alzheimer’s disease. Neurobiol Aging 36:2757–2767. doi:10.1016/j.neurobiolaging.2015.07.003

    Article  CAS  PubMed  Google Scholar 

  13. Frisch S, Dukart J, Vogt B, Horstmann A, Becker G, Villringer A, Barthel H, Sabri O, Müller K, Schroeter ML (2013) Dissociating memory networks in early Alzheimer’s disease and frontotemporal lobar degeneration—a combined study of hypometabolism and atrophy. PLoS One. doi:10.1371/journal.pone.0055251

    Google Scholar 

  14. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke EH, Bazan NG, Bertrand MJ, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Campanella M, Candi E, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin K-M, Di Daniele N, Dixit VM, Dynlacht BD, El-Deiry WS, Fimia GM, Flavell RA, Fulda S, Garrido C, Gougeon M-L, Green DR, Gronemeyer H, Hajnoczky G, Hardwick JM, Hengartner MO, Ichijo H, Joseph B, Jost PJ, Kaufmann T, Kepp O, Klionsky DJ, Knight RA, Kumar S, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lugli E, Madeo F, Malorni W, Marine J-C, Martin SJ, Martinou J-C, Medema JP, Meier P, Melino S, Mizushima N, Moll U, Muñoz-Pinedo C, Nuñez G, Oberst A, Panaretakis T, Penninger JM, Peter ME, Piacentini M, Pinton P, Prehn JH, Puthalakath H, Rabinovich GA, Ravichandran KS, Rizzuto R, Rodrigues CM, Rubinsztein DC, Rudel T, Shi Y, Simon H-U, Stockwell BR, Szabadkai G, Tait SW, Tang HL, Tavernarakis N, Tsujimoto Y, Vanden Berghe T, Vandenabeele P, Villunger A, Wagner EF, Walczak H, White E, Wood WG, Yuan J, Zakeri Z, Zhivotovsky B, Melino G, Kroemer G (2014) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. doi:10.1038/cdd.2014.137

    PubMed Central  Google Scholar 

  15. Guerrero-Muñoz MJ, Castillo-Carranza DL, Krishnamurthy S, Paulucci-Holthauzen AA, Sengupta U, Lasagna-Reeves CA, Ahmad Y, Jackson GR, Kayed R (2014) Amyloid-β oligomers as a template for secondary amyloidosis in Alzheimer’s disease. Neurobiol Dis 71:14–23. doi:10.1016/j.nbd.2014.08.008

    Article  CAS  PubMed  Google Scholar 

  16. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889. doi:10.1038/nature04724

    Article  CAS  PubMed  Google Scholar 

  17. Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18:794–799. doi:10.1038/nn.4017

    Article  CAS  PubMed  Google Scholar 

  18. Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3:77sr1

  19. Hornberger M, Piguet O, Graham AJ, Nestor PJ, Hodges JR (2010) How preserved is episodic memory in behavioural variant frontotemporal dementia. Neurology 74:473–479

    Article  Google Scholar 

  20. Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin-mediated endocytosis determines levels of the fronto-temporal dementia protein, progranulin. Neuron 68:654–667. doi:10.1016/j.jsbmb.2011.07.002.Identification

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hyman BT, Gomez-Isla T (1994) Alzheimer’s disease is a laminar, regional, and neural system specific disease, not a global brain disease. Neurobiol Aging 15:353–354

    Article  CAS  PubMed  Google Scholar 

  22. Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T, Malunda J, Xu Y, Winton MJ, Trojanowski JQ, Lee VMY (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738. doi:10.1172/JCI44867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Iguchi Y, Katsuno M, Niwa J, Takagi S, Ishigaki S, Ikenaka K, Kawai K, Watanabe H, Yamanaka K, Takahashi R, Misawa H, Sasaki S, Tanaka F, Sobue G (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136:1371–1382. doi:10.1093/brain/awt029

    Article  PubMed  Google Scholar 

  24. Inoue K, Rispoli J, Kaphzan H, Klann E, Chen EI, Kim J, Komatsu M, Abeliovich A (2012) Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. Mol Neurodegener 7:48. doi:10.1186/1750-1326-7-48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. International Parkinson Disease Genomics Consortium (2011) Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. PubMed—NCBI. Lancet 377:641–649

    Article  CAS  PubMed Central  Google Scholar 

  26. Jeong Y-H, Ling JP, Lin S, Donde A, Braunstein K, Majounie E, Traynor BJ, LaClair KD, Lloyd TE, Wong PC (2016) Tdp-43 cryptic exons are highly variable between cell types. Proc Natl Acad Sci (in review)

  27. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF, Ivnik RJ, Smith GE, Jack CR, Parisi JE, Petersen RC, Dickson DW (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127:811–824. doi:10.1007/s00401-014-1269-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack CR, Petersen RC, Dickson DW (2014) Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127:441–450. doi:10.1007/s00401-013-1211-9

    Article  CAS  PubMed  Google Scholar 

  29. Kadokura A, Yamazaki T, Lemere CA, Takatama M, Okamoto K (2009) Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology. Neuropathology 29:566–573. doi:10.1111/j.1440-1789.2009.01017.x

    Article  PubMed  Google Scholar 

  30. Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool S, Gurlo T, Butler P, Glabe CG (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18. doi:10.1186/1750-1326-2-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303. doi:10.1016/j.neuron.2009.06.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci 106:4012–4017. doi:10.1073/pnas.0811698106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kovacs GG, Milenkovic I, Wöhrer A, Höftberger R, Gelpi E, Haberler C, Hönigschnabl S, Reiner-Concin A, Heinzl H, Jungwirth S, Krampla W, Fischer P, Budka H (2013) Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol 126:365–384. doi:10.1007/s00401-013-1157-y

    Article  CAS  PubMed  Google Scholar 

  34. Kraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, Lee VMY, Schellenberg GD (2010) Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119:409–419. doi:10.1007/s00401-010-0659-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. LaClair KD, Manaye KF, Lee DL, Allard JS, Savonenko AV, Troncoso JC, Wong PC (2013) Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener 8:18. doi:10.1186/1750-1326-8-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ling JP, Pletnikova O, Troncoso JC, Wong PC (2015) TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science (80-) 349:650–655. doi:10.1126/science.aab0983

  37. Liu R, Yang G, Nonaka T, Arai T, Jia W, Cynader MS (2013) Reducing TDP-43 aggregation does not prevent its cytotoxicity. Acta Neuropathol Commun. doi:10.1186/2051-5960-1-49

    Google Scholar 

  38. Lu C, Fu W, Salvesen GS, Mattson MP (2002) Direct cleavage of AMPA receptor subunit GluR1 and suppression of AMPA currents by caspase-3: implications for synaptic plasticity and excitotoxic neuronal death. Neuromol Med 1:69–79. doi:10.1385/NMM:1:1:69

    Article  CAS  Google Scholar 

  39. Martin L, Kaiser A, Price A (1999) Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. J Neurobiol 40:185–201. doi:10.1002/(SICI)1097-4695(199908)40:2<185:AID-NEU5>3.0.CO;2-#

    Article  CAS  PubMed  Google Scholar 

  40. Morris GP, Clark IA, Vissel B (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2:135. doi:10.1186/s40478-014-0135-5

    PubMed  PubMed Central  Google Scholar 

  41. Musiek ES, Holtzman DM (2015) Three dimensions of the amyloid hypothesis: time, space and “wingmen”. Nat Neurosci 18:800–806. doi:10.1038/nn.4018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nadler JV, Perry BW, Cotman CW (1980) Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid. Brain Res 182:1–9

    Article  CAS  PubMed  Google Scholar 

  43. Neary D, Snowden J, Mann D, Bowen D, Sims N, Northen B, Yates P, Davidson A (1986) Alzheimer’s disease: a correlative study. J Neurol 49:229–237

    CAS  Google Scholar 

  44. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science (80-) 314:130–133. doi:10.1126/science.1134108

  45. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997. doi:10.1038/nm.3232

    Article  CAS  PubMed  Google Scholar 

  46. Parone PA, Da Druz S, Tondera D, Mattenberger Y, James DI, Maechler P, Barja F, Martinou JC (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS One 3:1–9. doi:10.1371/journal.pone.0003257

    Article  CAS  Google Scholar 

  47. Pennington C, Hodges JR, Hornberger M (2011) Neural correlates of episodic memory in behavioral variant frontotemporal dementia. J Alzheimers Dis 24:261–268. doi:10.3233/JAD-2011-101668

    PubMed  Google Scholar 

  48. Probst A, Tolnay M, Langui D, Goedert M, Spillantini MG (1996) Pick’s disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol 92:588–596

    Article  CAS  PubMed  Google Scholar 

  49. Rahimi J, Kovacs GG (2014) Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther 6:1–11. doi:10.1186/s13195-014-0082-1

    Article  Google Scholar 

  50. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EGP, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini M-L, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, Black SE, Mesulam M, Weintraub S, Dickerson BC, Diehl-Schmid J, Pasquier F, Deramecourt V, Lebert F, Pijnenburg Y, Chow TW, Manes F, Grafman J, Cappa SF, Freedman M, Grossman M, Miller BL (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477. doi:10.1093/brain/awr179

    Article  PubMed  PubMed Central  Google Scholar 

  51. Rosenblum WI (2014) Why Alzheimer trials fail: Removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult. Neurobiol Aging 35:969–974. doi:10.1016/j.neurobiolaging.2013.10.085

    Article  CAS  PubMed  Google Scholar 

  52. Scheff SW, Price DA (2006) Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis 9:101–115

    PubMed  Google Scholar 

  53. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. doi:10.1016/j.neurobiolaging.2005.09.012

    Article  CAS  PubMed  Google Scholar 

  54. Schmid B, Hruscha A, Hogl S, Banzhaf-strathmann J, Strecker K (2013) Loss of ALS-associated TDP-43 in zebra fish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. PNAS 110:4986–4991. doi:10.1073/pnas.1218311110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. doi:10.1126/science.1074069

    Article  CAS  PubMed  Google Scholar 

  56. Sephton CF, Good SK, Atkin S, Dewey CM, Mayer P, Herz J, Yu G (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285:6826–6834. doi:10.1074/jbc.M109.061846

    Article  CAS  PubMed  Google Scholar 

  57. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A (2016) The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537(7618):50–56. doi:10.1038/nature19323

    Article  CAS  PubMed  Google Scholar 

  58. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842. doi:10.1038/nm1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Snigdha S, Smith ED, Prieto GA, Cotman CW (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 28:14–24. doi:10.1007/s12264-012-1057-5

    Article  CAS  PubMed  Google Scholar 

  60. Stefanis L (2012) α-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009399. doi:10.1101/cshperspect.a009399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sze C-I, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer’s disease.pdf. J Neuropathol Exp Neurol 56:933–944

    Article  CAS  PubMed  Google Scholar 

  62. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. doi:10.1002/ana.410300410

    Article  CAS  PubMed  Google Scholar 

  63. Trougakos IP (2013) The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress: implications in therapeutic approaches—a mini-review. Gerontology 59:514–523. doi:10.1159/000351207

    Article  CAS  PubMed  Google Scholar 

  64. Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM-Y, Trojanowski JQ, Neumann M (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564. doi:10.1097/NEN.0b013e31817713b5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Walker AK, Spiller KJ, Ge G, Zheng A, Xu Y, Zhou M, Tripathy K, Kwong LK, Trojanowski JQ, Lee VM-Y (2015) Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol. doi:10.1007/s00401-015-1460-x

    Google Scholar 

  66. Wang W, Li L, Lin WL, Dickson DW, Petrucelli L, Zhang T, Wang X (2013) The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet 22:4706–4719. doi:10.1093/hmg/ddt319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wu LS, Cheng WC, Shen CKJ (2012) Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem 287:27335–27344. doi:10.1074/jbc.M112.359000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xie H, Guan J, Borrelli LA, Xu J, Serrano-Pozo A, Bacskai BJ (2013) Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model. J Neurosci 33:17042–17051. doi:10.1523/JNEUROSCI.1836-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang C, Wang H, Qiao T, Yang B, Aliaga L, Qiu L, Tan W, Salameh J, McKenna-Yasek DM, Smith T, Peng L, Moore MJ, Brown RH, Cai H, Xu Z (2014) Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc Natl Acad Sci 111:E1121–E1129. doi:10.1073/pnas.1322641111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zempel H, Thies E, Mandelkow E, Mandelkow E-M (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950. doi:10.1523/JNEUROSCI.2357-10.2010

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by the Johns Hopkins University School of Medicine Neuropathology Frederick J. Pelda Alzheimer’s Research Fund, the Robert Packard Center for ALS Research, the Amyotrophic Lateral Sclerosis Association, National Institute of Health grants R01-NS095969 and R01-NS079348, and the Johns Hopkins Alzheimer’s Disease Research Center (P50AG05146). The authors wish to thank Venette Nehus and Barbara Smith for technical assistance.

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Correspondence to Philip C. Wong.

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Johns Hopkins University School of Medicine Neuropathology Frederick J. Pelda Alzheimer’s Research Fund, the Robert Packard Center for ALS Research, the Amyotrophic Lateral Sclerosis Association, National Institute of Health grants R01-NS095969 and R01-NS079348, and the Johns Hopkins Alzheimer’s Disease Research Center (P50AG05146).

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The authors declare no competing financial interests.

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All animal studies were performed in accordance with institutional guidelines and the laws of the United States of America. No research involved human participants in this study.

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LaClair, K.D., Donde, A., Ling, J.P. et al. Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model. Acta Neuropathol 132, 859–873 (2016). https://doi.org/10.1007/s00401-016-1637-y

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