Review: Axon pathology in age-related neurodegenerative disorders

Neuropathology and Applied Neurobiology

Volumn 39, Issue 2, 2013, Pages 90-108

  Adalbert, R ^a   Coleman, M P ^a  

^a BABRAHAM INSTITUTE   (United Kingdom)

Author keywords

Ageing; Alzheimer's disease; Amyotrophic lateral sclerosis; Axon degeneration; Glaucoma; Parkinson's disease

Indexed keywords

1 METHYL 4 PHENYLPYRIDINIUM; 1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; CALCIUM ION; COPPER ZINC SUPEROXIDE DISMUTASE; GAMMA SECRETASE; GLYCOGEN SYNTHASE KINASE 3BETA; LEUCINE RICH REPEAT KINASE 2; MITOCHONDRIAL DNA; PARKIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PRESENILIN 1; PRESENILIN 2; PROFILIN; PROFILIN I; PROTEIN KINASE B; PTEN INDUCED KINASE 1; TAR DNA BINDING PROTEIN; TAU PROTEIN; TYROSINE 3 MONOOXYGENASE; UNCLASSIFIED DRUG; WNT PROTEIN;

AGING; ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; AUTOPHAGY; BRAIN MITOCHONDRION; CALCIUM SIGNALING; CELL ORGANELLE; DEGENERATIVE DISEASE; DENDRITE; DOPAMINERGIC NERVE CELL; ENDOPLASMIC RETICULUM STRESS; GENE MUTATION; GENE OVEREXPRESSION; GLAUCOMA; GLIA; HISTOPATHOLOGY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INCIDENCE; INTRAOCULAR HYPERTENSION; INTRAOCULAR PRESSURE; MOLECULAR BIOLOGY; MOLECULAR PATHOLOGY; MOTONEURON; NERVE CELL PLASTICITY; NERVE FIBER; NERVE FIBER TRANSPORT; NERVOUS SYSTEM; NEUROPATHOLOGY; NONHUMAN; PARKINSON DISEASE; PREVALENCE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; RISK FACTOR; SIGNAL TRANSDUCTION; SYMPTOM; SYNAPSE; TRAUMATIC BRAIN INJURY; WHITE MATTER; PATHOLOGY;

AGING; ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; AXONS; GLAUCOMA; HUMANS; PARKINSON DISEASE;

EID: 84873053822     PISSN: 03051846     EISSN: 13652990     Source Type: Journal    
DOI: 10.1111/j.1365-2990.2012.01308.x     Document Type: Article

References (176)

1. Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA, Kerschensteiner M, Misgeld T, Coleman MP. Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 2009; 132: 402-416
2. Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 2004; 7: 1181-1183
3. Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 2005; 25: 7278-7287
4. Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol (Berl) 2008; 115: 5-38
5. Cummings BJ, Head E, Ruehl W, Milgram NW, Cotman CW. The canine as an animal model of human aging and dementia. Neurobiol Aging 1996; 17: 259-268
6. Martin LJ, Sisodia SS, Koo EH, Cork LC, Dellovade TL, Weidemann A, Beyreuther K, Masters C, Price DL. Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci U S A 1991; 88: 1461-1465
7. Lazarov O, Lee M, Peterson DA, Sisodia SS. Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 2002; 22: 9785-9793
8. Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease. Acta Neuropathol (Berl) 2006; 111: 312-319
9. Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 2010; 13: 190-196
10. Zhang XM, Cai Y, Xiong K, Cai H, Luo XG, Feng JC, Clough RW, Struble RG, Patrylo PR, Yan XX. Beta-secretase-1 elevation in transgenic mouse models of Alzheimer's disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development. Eur J Neurosci 2009; 30: 2271-2283
11. Zhang XM, Xiong K, Cai Y, Cai H, Luo XG, Feng JC, Clough RW, Patrylo PR, Struble RG, Yan XX. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex. Eur J Neurosci 2010; 31: 710-721
12. Cai Y, Zhang XM, Macklin LN, Cai H, Luo XG, Oddo S, Laferla FM, Struble RG, Rose GM, Patrylo PR, Yan XX. BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential Abeta antibody labeling of early-onset axon terminal pathology. Neurotox Res 2012; 21: 160-174
13. Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M. Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J Neurochem 2005; 94: 1189-1201
14. Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Goate A, Wolfe MS, Shearman M, Kopan R. A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A 2003; 100: 13075-13080
15. Cervantes S, Saura CA, Pomares E, Gonzalez-Duarte R, Marfany G. Functional implications of the presenilin dimerization: reconstitution of gamma-secretase activity by assembly of a catalytic site at the dimer interface of two catalytically inactive presenilins. J Biol Chem 2004; 279: 36519-36529
16. Peethumnongsin E, Yang L, Kallhoff-Munoz V, Hu L, Takashima A, Pautler RG, Zheng H. Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function. J Neurosci 2010; 30: 13409-13418
17. Kawamura Y, Kikuchi A, Takada R, Takada S, Sudoh S, Shibamoto S, Yanagisawa K, Komano H. Inhibitory effect of a presenilin 1 mutation on the Wnt signalling pathway by enhancement of beta-catenin phosphorylation. Eur J Biochem 2001; 268: 3036-3041
18. Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest 2007; 117: 1230-1239
19. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781-810
20. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis - a look outside the nucleus. Science 2000; 287: 1606-1609
21. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet 2011; 20: 4515-4529
22. Llorens-Martin M, Lopez-Domenech G, Soriano E, Avila J. GSK3beta is involved in the relief of mitochondria pausing in a Tau-dependent manner. PLoS ONE 2011; 6: e27686
23. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L. Tau reduction prevents Abeta-induced defects in axonal transport. Science 2010; 330: 198
24. Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP, Wade-Martins R, Paulsen O, Vargas-Caballero M. Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci 2011; 31: 1688-1692
25. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wolfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Gotz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010; 142: 387-397
26. Di Paola M, Spalletta G, Caltagirone C. In vivo structural neuroanatomy of corpus callosum in Alzheimer's disease and mild cognitive impairment using different MRI techniques: a review. J Alzheimers Dis 2010; 20: 67-95
27. Di Paola M, Di Iulio F, Cherubini A, Blundo C, Casini AR, Sancesario G, Passafiume D, Caltagirone C, Spalletta G. When, where, and how the corpus callosum changes in MCI and AD: a multimodal MRI study. Neurology 2010; 74: 1136-1142
28. Aboitiz F, Rodriguez E, Olivares R, Zaidel E. Age-related changes in fibre composition of the human corpus callosum: sex differences. Neuroreport 1996; 7: 1761-1764
29. Aboitiz F, Scheibel AB, Fisher RS, Zaidel E. Fiber composition of the human corpus callosum. Brain Res 1992; 598: 143-153
30. Arendt T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol (Berl) 2009; 118: 167-179
31. Davies CA, Mann DM, Sumpter PQ, Yates PO. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J Neurol Sci 1987; 78: 151-164
32. Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 2007; 68: 1501-1508
33. Grutzendler J, Helmin K, Tsai J, Gan WB. Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer's disease. Ann N Y Acad Sci 2007; 1097: 30-39
34. Sanchez-Varo R, Trujillo-Estrada L, Sanchez-Mejias E, Torres M, Baglietto-Vargas D, Moreno-Gonzalez I, De Castro V, Jimenez S, Ruano D, Vizuete M, Davila JC, Garcia-Verdugo JM, Jimenez AJ, Vitorica J, Gutierrez A. Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer's mice hippocampus. Acta Neuropathol (Berl) 2012; 123: 53-70
35. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010; 141: 1146-1158
36. Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, St George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 2011; 134: 258-277
37. Van Den Heuvel C, Thornton E, Vink R. Traumatic brain injury and Alzheimer's disease: a review. Prog Brain Res 2007; 161: 303-316
38. Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 2003; 74: 857-862
39. Geddes JF, Vowles GH, Beer TW, Ellison DW. The diagnosis of diffuse axonal injury: implications for forensic practice. Neuropathol Appl Neurobiol 1997; 23: 339-347
40. Geddes JF, Whitwell HL, Graham DI. Traumatic axonal injury: practical issues for diagnosis in medicolegal cases. Neuropathol Appl Neurobiol 2000; 26: 105-116
41. Roberts GW, Gentleman SM, Lynch A, Graham D. I. beta A4 amyloid protein deposition in brain after head trauma. Lancet 1991; 338: 1422-1423
42. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1994; 57: 419-425
43. Chen XH, Johnson VE, Uryu K, Trojanowski JQ, Smith DH. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol 2009; 19: 214-223
44. Johnson VE, Stewart W, Smith DH. Widespread tau and amyloid-Beta pathology many years after a single traumatic brain injury in humans. Brain Pathol 2012; 22: 142-149
45. Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer's disease? Nat Rev Neurosci 2010; 11: 361-370
46. Smith DH, Chen XH, Nonaka M, Trojanowski JQ, Lee VM, Saatman KE, Leoni MJ, Xu BN, Wolf JA, Meaney DF. Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol 1999; 58: 982-992
47. Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH. Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol 2004; 165: 357-371
48. Uryu K, Chen XH, Martinez D, Browne KD, Johnson VE, Graham DI, Lee VM, Trojanowski JQ, Smith DH. Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 2007; 208: 185-192
49. Maxwell WL, Domleo A, McColl G, Jafari SS, Graham DI. Post-acute alterations in the axonal cytoskeleton after traumatic axonal injury. J Neurotrauma 2003; 20: 151-168
50. Smith DH, Uryu K, Saatman KE, Trojanowski JQ, McIntosh TK. Protein accumulation in traumatic brain injury. Neuromolecular Med 2003; 4: 59-72
51. Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, Clark RS, Marion DW, Wisniewski SR, DeKosky ST. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol 2004; 190: 192-203
52. Tran HT, LaFerla FM, Holtzman DM, Brody DL. Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J Neurosci 2011; 31: 9513-9525
53. Tran HT, Sanchez L, Esparza TJ, Brody DL. Distinct temporal and anatomical distributions of amyloid-beta and tau abnormalities following controlled cortical impact in transgenic mice. PLoS ONE 2011; 6: e25475
54. Burke RE, O'Malley K. Axon degeneration in Parkinson's disease. Exp Neurol 2012; doi: 10.1016/j.expneurol.2012.01.011
55. Driver JA, Logroscino G, Gaziano JM, Kurth T. Incidence and remaining lifetime risk of Parkinson disease in advanced age. Neurology 2009; 72: 432-438
56. Greene LA, Levy O, Malagelada C. Akt as a victim, villain and potential hero in Parkinson's disease pathophysiology and treatment. Cell Mol Neurobiol 2011; 31: 969-978
57. Kim SR, Ries V, Cheng HC, Kareva T, Oo TF, Yu WH, Duff K, Kholodilov N, Burke RE. Age and alpha-synuclein expression interact to reveal a dependence of dopaminergic axons on endogenous Akt/PKB signaling. Neurobiol Dis 2011; 44: 215-222
58. Pals P, Lincoln S, Manning J, Heckman M, Skipper L, Hulihan M, Van den Broeck M, De Pooter T, Cras P, Crook J, Van Broeckhoven C, Farrer MJ. alpha-Synuclein promoter confers susceptibility to Parkinson's disease. Ann Neurol 2004; 56: 591-595
59. Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A 2005; 102: 18676-18681
60. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005; 102: 16842-16847
61. Lin CH, Tsai PI, Wu RM, Chien CT. LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ss. J Neurosci 2010; 30: 13138-13149
62. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE 2011; 6: e18568
63. Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 2009; 12: 826-828
64. Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM, Trojanowski JQ. Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol (Berl) 2002; 104: 7-11
65. Kim-Han JS, Antenor-Dorsey JA, O'Malley KL. The Parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J Neurosci 2011; 31: 7212-7221
66. Arnold B, Cassady SJ, VanLaar VS, Berman SB. Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model. Neurobiol Dis 2011; 41: 189-200
67. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183: 795-803
68. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010; 8: e1000298
69. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 2011; 147: 893-906
70. Cai Q, Zakaria HM, Simone A, Sheng ZH. Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr Biol 2012; 22: 545-552
71. Maday S, Wallace KE, Holzbaur EL. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J Cell Biol 2012; 196: 407-417
72. Williamson TL, Cleveland DW. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 1999; 2: 50-56
73. De Vos KJ, Chapman AL, Tennant ME, Manser C, Tudor EL, Lau KF, Brownlees J, Ackerley S, Shaw PJ, McLoughlin DM, Shaw CE, Leigh PN, Miller CC, Grierson AJ. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet 2007; 16: 2720-2728
74. De Vos KJ, Grierson AJ, Ackerley S, Miller CC. Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci 2008; 31: 151-173
75. Bilsland LG, Sahai E, Kelly G, Golding M, Greensmith L, Schiavo G. Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A 2010; 107: 20523-20528
76. Marinkovic P, Reuter MS, Brill MS, Godinho L, Kerschensteiner M, Misgeld T. Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2012; 109: 4296-4301
77. Brady ST. Sluggish Mitochondria Not Causing Withered ALS Axons After All? Alzforum. 2012. Available at: http://www.alzforum.org/new/detail.asp?id=3091 (last accessed 23 October 2012)
78. Pun S, Santos AF, Saxena S, Xu L, Caroni P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 2006; 9: 408-419
79. Vande Velde C, McDonald KK, Boukhedimi Y, McAlonis-Downes M, Lobsiger CS, Bel Hadj S, Zandona A, Julien JP, Shah SB, Cleveland DW. Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS ONE 2011; 6: e22031
80. Zhu YB, Sheng ZH. Increased axonal mitochondrial mobility does not slow amyotrophic lateral sclerosis (ALS)-like disease in mutant SOD1 mice. J Biol Chem 2011; 286: 23432-23440
81. Kang JS, Tian JH, Pan PY, Zald P, Li C, Deng C, Sheng ZH. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 2008; 132: 137-148
82. Saxena S, Cabuy E, Caroni P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci 2009; 12: 627-636
83. Valdez G, Tapia JC, Kang H, Clemenson GD Jr, Gage FH, Lichtman JW, Sanes JR. Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc Natl Acad Sci U S A 2010; 107: 14863-14868
84. Lagier-Tourenne C, Polymenidou M, Cleveland DW. TDP-43 and FUS/TLS: emerging roles in RNA process ing and neurodegeneration. Hum Mol Genet 2010; 19: R46-64
85. Murakami T, Yang SP, Xie L, Kawano T, Fu D, Mukai A, Bohm C, Chen F, Robertson J, Suzuki H, Tartaglia GG, Vendruscolo M, Kaminski Schierle GS, Chan FT, Moloney A, Crowther D, Kaminski CF, Zhen M, St George-Hyslop P. ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism. Hum Mol Genet 2012; 21: 1-9
86. Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 2010; 107: 3858-3863
87. Cohen TJ, Lee VM, Trojanowski JQ. TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med 2011; 17: 659-667
88. Fallini C, Bassell GJ, Rossoll W. The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth. Hum Mol Genet 2012; 21: 3703-3718
89. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 2012; 488: 499-503
90. Nickells RW, Howell GR, Soto I, John SW. Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. Annu Rev Neurosci 2012; 35: 153-179
91. Dandona L, Hendrickson A, Quigley HA. Selective effects of experimental glaucoma on axonal transport by retinal ganglion cells to the dorsal lateral geniculate nucleus. Invest Ophthalmol Vis Sci 1991; 32: 1593-1599
92. Radius RL, Anderson DR. Morphology of axonal transport abnormalities in primate eyes. Br J Ophthalmol 1981; 65: 767-777
93. Martin KR, Quigley HA, Valenta D, Kielczewski J, Pease ME. Optic nerve dynein motor protein distribution changes with intraocular pressure elevation in a rat model of glaucoma. Exp Eye Res 2006; 83: 255-262
94. Chidlow G, Ebneter A, Wood JP, Casson RJ. The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma. Acta Neuropathol (Berl) 2011; 121: 737-751
95. Crish SD, Sappington RM, Inman DM, Horner PJ, Calkins DJ. Distal axonopathy with structural persistence in glaucomatous neurodegeneration. Proc Natl Acad Sci U S A 2010; 107: 5196-5201
96. Whitmore AV, Libby RT, John SW. Glaucoma: thinking in new ways-a role for autonomous axonal self-destruction and other compartmentalised processes? Prog Retin Eye Res 2005; 24: 639-662
97. Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 2007; 179: 1523-1537
98. Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW. Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci 2006; 7: 66
99. Beirowski B, Babetto E, Coleman MP, Martin KR. The WldS gene delays axonal but not somatic degeneration in a rat glaucoma model. Eur J Neurosci 2008; 28: 1166-1179
100. Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D, Thomson D, Gillingwater T, Court F, Conforti L, Fernando FS, Tarlton A, Andressen C, Addicks K, Magni G, Ribchester RR, Perry VH, Coleman MP. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat Neurosci 2001; 4: 1199-1206
101. Adalbert R, Gillingwater TH, Haley JE, Bridge K, Beirowski B, Berek L, Wagner D, Grumme D, Thomson D, Celik A, Addicks K, Ribchester RR, Coleman MP. A rat model of slow Wallerian degeneration (WldS) with improved preservation of neuromuscular synapses. Eur J Neurosci 2005; 21: 271-277
102. Bull ND, Chidlow G, Wood JP, Martin KR, Casson RJ. The mechanism of axonal degeneration after perikaryal excitotoxic injury to the retina. Exp Neurol 2012; 236: 34-45
103. Pakkenberg B, Gundersen HJ. Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 1997; 384: 312-320
104. Selkoe DJ. Alzheimer's disease is a synaptic failure. Science 2002; 298: 789-791
105. Marner L, Nyengaard JR, Tang Y, Pakkenberg B. Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol 2003; 462: 144-152
106. Morrison JH, Baxter MG. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 2012; 13: 240-250
107. Soghomonian JJ, Sethares C, Peters A. Effects of age on axon terminals forming axosomatic and axodendritic inhibitory synapses in prefrontal cortex. Neuroscience 2010; 168: 74-81
108. Bowley MP, Cabral H, Rosene DL, Peters A. Age changes in myelinated nerve fibers of the cingulate bundle and corpus callosum in the rhesus monkey. J Comp Neurol 2010; 518: 3046-3064
109. Sandell JH, Peters A. Disrupted myelin and axon loss in the anterior commissure of the aged rhesus monkey. J Comp Neurol 2003; 466: 14-30
110. Cepurna WO, Kayton RJ, Johnson EC, Morrison JC. Age related optic nerve axonal loss in adult Brown Norway rats. Exp Eye Res 2005; 80: 877-884
111. Sandell JH, Peters A. Effects of age on nerve fibers in the rhesus monkey optic nerve. J Comp Neurol 2001; 429: 541-553
112. Samuel MA, Zhang Y, Meister M, Sanes JR. Age-related alterations in neurons of the mouse retina. J Neurosci 2011; 31: 16033-16044
113. Jacobs JM, Love S. Qualitative and quantitative morphology of human sural nerve at different ages. Brain 1985; 108 (Pt 4): 897-924
114. Chang YC, Lin WM, Hsieh ST. Effects of aging on human skin innervation. Neuroreport 2004; 15: 149-153
115. Chambers JK, Uchida K, Nakayama H. White matter myelin loss in the brains of aged dogs. Exp Gerontol 2012; 47: 263-269
116. Ceballos D, Cuadras J, Verdu E, Navarro X. Morphometric and ultrastructural changes with ageing in mouse peripheral nerve. J Anat 1999; 195 (Pt 4): 563-576
117. Jang YC, Van Remmen H. Age-associated alterations of the neuromuscular junction. Exp Gerontol 2011; 46: 193-198
118. Richard MB, Taylor SR, Greer CA. Age-induced disruption of selective olfactory bulb synaptic circuits. Proc Natl Acad Sci U S A 2010; 107: 15613-15618
119. Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 2010; 30: 7507-7515
120. Andersen BB, Gundersen HJ, Pakkenberg B. Aging of the human cerebellum: a stereological study. J Comp Neurol 2003; 466: 356-365
121. Huang CM, Brown N, Huang RH. Age-related changes in the cerebellum: parallel fibers. Brain Res 1999; 840: 148-152
122. Toth ML, Melentijevic I, Shah L, Bhatia A, Lu K, Talwar A, Naji H, Ibanez-Ventoso C, Ghose P, Jevince A, Xue J, Herndon LA, Bhanot G, Rongo C, Hall DH, Driscoll M. Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. J Neurosci 2012; 32: 8778-8790
123. Chen J, Mizushige T, Nishimune H. Active zone density is conserved during synaptic growth but impaired in aged mice. J Comp Neurol 2012; 520: 434-452
124. Kimura N, Okabayashi S, Ono F. Dynein dysfunction disrupts intracellular vesicle trafficking bidirectionally and perturbs synaptic vesicle docking via endocytic disturbances a potential mechanism underlying age-dependent impairment of cognitive function. Am J Pathol 2012; 180: 550-561
125. Golde TE, Miller VM. Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases. Alzheimers Res Ther 2009; 1: 5
126. Valdez G, Tapia JC, Lichtman JW, Fox MA, Sanes JR. Shared resistance to aging and ALS in neuromuscular junctions of specific muscles. PLoS ONE 2012; 7: e34640
127. Balice-Gordon RJ. Age-related changes in neuromuscular innervation. Muscle Nerve Suppl 1997; 5: S83-87
128. Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B. Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol Appl Neurobiol 2002; 28: 283-291
129. Rudow G, O'Brien R, Savonenko AV, Resnick SM, Zonderman AB, Pletnikova O, Marsh L, Dawson TM, Crain BJ, West MJ, Troncoso JC. Morphometry of the human substantia nigra in ageing and Parkinson's disease. Acta Neuropathol (Berl) 2008; 115: 461-470
130. Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 2009; 29: 444-453
131. Wolf ME, LeWitt PA, Bannon MJ, Dragovic LJ, Kapatos G. Effect of aging on tyrosine hydroxylase protein content and the relative number of dopamine nerve terminals in human caudate. J Neurochem 1991; 56: 1191-1200
132. Chen S, Hillman DE. Dying-back of Purkinje cell dendrites with synapse loss in aging rats. J Neurocytol 1999; 28: 187-196
133. Rubinow MJ, Drogos LL, Juraska JM. Age-related dendritic hypertrophy and sexual dimorphism in rat basolateral amygdala. Neurobiol Aging 2009; 30: 137-146
134. Pyapali GK, Turner DA. Increased dendritic extent in hippocampal CA1 neurons from aged F344 rats. Neurobiol Aging 1996; 17: 601-611
135. Eliasieh K, Liets LC, Chalupa LM. Cellular reorganization in the human retina during normal aging. Invest Ophthalmol Vis Sci 2007; 48: 2824-2830
136. Tank EM, Rodgers KE, Kenyon C. Spontaneous age-related neurite branching in Caenorhabditis elegans. J Neurosci 2011; 31: 9279-9288
137. Coleman M. Molecular signaling how do axons die? Adv Genet 2011; 73: 185-217
138. Gilley J, Seereeram A, Ando K, Mosely S, Andrews S, Kerschensteiner M, Misgeld T, Brion JP, Anderton B, Hanger DP, Coleman MP. Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a 'P301L' tau knockin mouse. Neurobiol Aging 2011; 33: 621e1-15
139. Bridge KE, Berg N, Adalbert R, Babetto E, Dias T, Spillantini MG, Ribchester RR, Coleman MP. Late onset distal axonal swelling in YFP-H transgenic mice. Neurobiol Aging 2009; 30: 309-321
140. Kimura N, Imamura O, Ono F, Terao K. Aging attenuates dynactin-dynein interaction: down-regulation of dynein causes accumulation of endogenous tau and amyloid precursor protein in human neuroblastoma cells. J Neurosci Res 2007; 85: 2909-2916
141. Soong NW, Hinton DR, Cortopassi G, Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet 1992; 2: 318-323
142. Court FA, Coleman MP. Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci 2012; 35: 364-372
143. Pannese E. Morphological changes in nerve cells during normal aging. Brain Struct Funct 2011; 216: 85-89
144. Shields SA, Gilson JM, Blakemore WF, Franklin RJ. Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 1999; 28: 77-83
145. Setzu A, Ffrench-Constant C, Franklin RJ. CNS axons retain their competence for myelination throughout life. Glia 2004; 45: 307-311
146. Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJ. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 2012; 10: 96-103
147. Zhao C, Fancy SP, Kotter MR, Li WW, Franklin RJ. Mechanisms of CNS remyelination - the key to therapeutic advances. J Neurol Sci 2005; 233: 87-91
148. Kotter MR, Zhao C, van Rooijen N, Franklin RJ. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 2005; 18: 166-175
149. Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadinanos J, Horner JW, Maratos-Flier E, Depinho RA. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011; 469: 102-106
150. Jaerve A, Schiwy N, Schmitz C, Mueller HW. Differential effect of aging on axon sprouting and regenerative growth in spinal cord injury. Exp Neurol 2011; 231: 284-294
151. Verdu E, Ceballos D, Vilches JJ, Navarro X. Influence of aging on peripheral nerve function and regeneration. J Peripher Nerv Syst 2000; 5: 191-208
152. Burke SN, Barnes CA. Senescent synapses and hippocampal circuit dynamics. Trends Neurosci 2010; 33: 153-161
153. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Despres S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011; 477: 90-94
154. Collier TJ, Kanaan NM, Kordower JH. Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat Rev Neurosci 2011; 12: 359-366
155. Ryan L, Walther K, Bendlin BB, Lue LF, Walker DG, Glisky EL. Age-related differences in white matter integrity and cognitive function are related to APOE status. Neuroimage 2011; 54: 1565-1577
156. Kinnunen K, Petrovski G, Moe MC, Berta A, Kaarniranta K. Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol (Copenh) 2012; 90: 299-309
157. Probst A, Gotz J, Wiederhold KH, Tolnay M, Mistl C, Jaton AL, Hong M, Ishihara T, Lee VM, Trojanowski JQ, Jakes R, Crowther RA, Spillantini MG, Burki K, Goedert M. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol (Berl) 2000; 99: 469-481
158. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000; 157: 267-276
159. Tollervey JR, Wang Z, Hortobagyi T, Witten JT, Zarnack K, Kayikci M, Clark TA, Schweitzer AC, Rot G, Curk T, Zupan B, Rogelj B, Shaw CE, Ule J. Analysis of alternative splicing associated with aging and neurodegeneration in the human brain. Genome Res 2011; 21: 1572-1582
160. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991; 114 (Pt 5): 2283-2301
161. Wolk DA, Klunk W. Update on amyloid imaging: from healthy aging to Alzheimer's disease. Curr Neurol Neurosci Rep 2009; 9: 345-352
162. Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 1988; 23: 138-144
163. Langston JW, Ballard PA Jr. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine. N Engl J Med 1983; 309: 310
164. Stephan BC, Matthews FE, Ma B, Muniz G, Hunter S, Davis D, McKeith IG, Foster G, Ince PG, Brayne C. Alzheimer and vascular neuropathological changes associated with different cognitive States in a non-demented sample. J Alzheimers Dis 2012; 29: 309-318
165. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006; 66: 1837-1844
166. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 2005; 307: 1282-1288
167. Gonitel R, Moffitt H, Sathasivam K, Woodman B, Detloff PJ, Faull RL, Bates GP. DNA instability in postmitotic neurons. Proc Natl Acad Sci U S A 2008; 105: 3467-3472
168. Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A. Autophagy and aging: the importance of maintaining 'clean' cells. Autophagy 2005; 1: 131-140
169. Rist JM, Franklin RJ. Taking ageing into account in remyelination-based therapies for multiple sclerosis. J Neurol Sci 2008; 274: 64-67
170. Perry VH, Newman TA, Cunningham C. The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 2003; 4: 103-112
171. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009; 132: 1175-1189
172. Weller RO, Djuanda E, Yow HY, Carare RO. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol (Berl) 2009; 117: 1-14
173. Hamner MA, Moller T, Ransom BR. Anaerobic function of CNS white matter declines with age. J Cereb Blood Flow Metab 2011; 31: 996-1002
174. Lupi D, Semo M, Foster RG. Impact of age and retinal degeneration on the light input to circadian brain structures. Neurobiol Aging 2012; 33: 383-392
175. Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci 2010; 11: 589-599
176. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25: 9275-9284