Substantial progress has been made toward understanding the neuropathology, genetic origins, and epidemiology of neurodegenerative diseases, including Alzheimer's disease; tauopathies, such as frontotemporal dementia; α-synucleinopathies, such as Parkinson's disease or dementia with Lewy bodies; Huntington's disease; and amyotrophic lateral sclerosis with dementia, as well as prion diseases. Recent evidence has implicated dendritic spine dysfunction as an important substrate of the pathogenesis of dementia in these disorders. Dendritic spines are specialized structures, extending from the neuronal processes, on which excitatory synaptic contacts are formed, and the loss of dendritic spines correlates with the loss of synaptic function. We review the literature that has implicated direct or indirect structural alterations at dendritic spines in the pathogenesis of major neurodegenerative diseases, focusing on those that lead to dementias such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as frontotemporal dementia and prion diseases. We stress the importance of in vivo studies in animal models.


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Literature Cited

  1. Fu M, Zuo Y. 1.  2011. Experience-dependent structural plasticity in the cortex. Trends Neurosci. 34:177–87 [Google Scholar]
  2. Rocher AB, Kinson MS, Luebke JI. 2.  2008. Significant structural but not physiological changes in cortical neurons of 12-month-old Tg2576 mice. Neurobiol. Dis. 32:309–18 [Google Scholar]
  3. Yuste R, Bonhoeffer T. 3.  2004. Genesis of dendritic spines: insights from ultrastructural and imaging studies. Nat. Rev. Neurosci. 5:24–34 [Google Scholar]
  4. Holtmaat AJGD, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X. 4.  et al. 2005. Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45:279–91 [Google Scholar]
  5. Grutzendler J, Kasthuri N, Gan WB. 5.  2002. Long-term dendritic spine stability in the adult cortex. Nature 420:812–16 [Google Scholar]
  6. Schikorski T, Stevens CF. 6.  1999. Quantitative fine-structural analysis of olfactory cortical synapses. PNAS 96:4107–12 [Google Scholar]
  7. Yuste R, Bonhoeffer T. 7.  2001. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24:1071–89 [Google Scholar]
  8. Lendvai B, Stern EA, Chen B, Svoboda K. 8.  2000. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Nature 404:876–81 [Google Scholar]
  9. Yang G, Pan F, Gan W-B. 9.  2009. Stably maintained dendritic spines are associated with lifelong memories. Nature 462:920–24 [Google Scholar]
  10. Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA. 10.  et al. 2009. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462:915–19 [Google Scholar]
  11. Mostany R, Anstey JE, Crump KL, Maco B, Knott G, Portera-Cailliau C. 11.  2013. Altered synaptic dynamics during normal brain aging. J. Neurosci. 33:4094–104 [Google Scholar]
  12. Jung CKE, Herms J. 12.  2014. Structural dynamics of dendritic spines are influenced by an environmental enrichment: an in vivo imaging study. Cereb. Cortex 24:377–84 [Google Scholar]
  13. Falkenberg T, Mohammed AK, Henriksson B, Persson H, Winblad B, Lindefors N. 13.  1992. Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci. Lett. 138:153–56 [Google Scholar]
  14. Beaulieu J-M, Gainetdinov RR, Caron MG. 14.  2009. Akt/GSK3 signaling in the action of psychotropic drugs. Annu. Rev. Pharmacol. Toxicol. 49:327–47 [Google Scholar]
  15. Dewachter I, Ris L, Jaworski T, Seymour CM, Kremer A. 15.  et al. 2009. GSK3β, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9. Neurobiol. Dis. 35:193–200 [Google Scholar]
  16. Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L. 16.  et al. 2007. LTP inhibits LTD in the hippocampus via regulation of GSK3β. Neuron 53:703–17 [Google Scholar]
  17. Ochs SM, Dorostkar MM, Aramuni G, Schon C, Filser S. 17.  et al. 2014. Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin. Mol. Psychiatry 20:482–89 [Google Scholar]
  18. Shirao T, González-Billault C. 18.  2013. Actin filaments and microtubules in dendritic spines. J. Neurochem. 126:155–64 [Google Scholar]
  19. Thomas MG, Pascual ML, Maschi D, Luchelli L, Boccaccio GL. 19.  2014. Synaptic control of local translation: The plot thickens with new characters. Cell. Mol. Life Sci. 71:2219–39 [Google Scholar]
  20. Rahimi F, Bitan G. 20.  2012. Non-Fibrillar Amyloidogenic Protein Assemblies—Common Cytotoxins Underlying Degenerative Diseases Dordrecht, Neth.: Springer [Google Scholar]
  21. Golgi C. 21.  1873. Sulla struttura della sostanza grigia del cervello (comunicazione preventiva). Gazz. Med. Ital. Lomb. 33:244–46 [Google Scholar]
  22. Desmond NL, Levy WB. 22.  1985. Granule cell dendritic spine density in the rat hippocampus varies with spine shape and location. Neurosci. Lett. 54:219–24 [Google Scholar]
  23. Andrade JP, Madeira MD, Paula-Barbosa MM. 23.  1998. Differential vulnerability of the subiculum and entorhinal cortex of the adult rat to prolonged protein deprivation. Hippocampus 8:33–47 [Google Scholar]
  24. Andrade JP, Castanheira-Vale AJ, Paz-Dias PG, Madeira MD, Paula-Barbosa MM. 24.  1996. The dendritic trees of neurons from the hippocampal formation of protein-deprived adult rats. A quantitative Golgi study. Exp. Brain Res. 109:419–33 [Google Scholar]
  25. Ramón y Cajal S. 25.  1991. Cajal's Degeneration and Regeneration of the Nervous System New York: Oxford Univ. Press [Google Scholar]
  26. Holtmaat A, Randall J, Cane M. 26.  2013. Optical imaging of structural and functional synaptic plasticity in vivo. Eur. J. Pharmacol. 719:128–36 [Google Scholar]
  27. Maco B, Holtmaat A, Jorstad A, Fua P, Knott GW. 27.  2014. Correlative in vivo 2-photon imaging and focused ion beam scanning electron microscopy: 3D analysis of neuronal ultrastructure. Methods Cell Biol. 124:339–61 [Google Scholar]
  28. Blazquez-Llorca L, Hummel E, Zimmerman H, Zou C, Burgold S. 28.  et al. 2015. Correlation of two-photon in vivo imaging and FIB/SEM microscopy. J. Microsc. 259:129–36 [Google Scholar]
  29. Murthy VN, Schikorski T, Stevens CF, Zhu Y. 29.  2001. Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32:673–82 [Google Scholar]
  30. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS. 30.  2000. PSD-95 involvement in maturation of excitatory synapses. Science 290:1364–68 [Google Scholar]
  31. Biesemann C, Gronborg M, Luquet E, Wichert SP, Bernard V. 31.  et al. 2014. Proteomic screening of glutamatergic mouse brain synaptosomes isolated by fluorescence activated sorting. EMBO J. 33:157–70 [Google Scholar]
  32. Coleman PD, Riesen AH. 32.  1968. Environmental effects on cortical dendritic fields. I. Rearing in the dark. J. Anat. 102:363–74 [Google Scholar]
  33. Jones WH, Thomas DB. 33.  1962. Changes in the dendritic organization of neurons in the cerebral cortex following deafferentation. J. Anat. 96:375–81 [Google Scholar]
  34. Matthews MR, Powell TPS. 34.  1962. Some observations on transneuronal cell degeneration in the olfactory bulb of the rabbit. J. Anat. 96:89–102.3 [Google Scholar]
  35. Keck T, Mrsic-Flogel TD, Vaz Afonso M, Eysel UT, Bonhoeffer T, Hubener M. 35.  2008. Massive restructuring of neuronal circuits during functional reorganization of adult visual cortex. Nat. Neurosci. 11:1162–67 [Google Scholar]
  36. Halpain S, Hipolito A, Saffer L. 36.  1998. Regulation of F-actin stability in dendritic spines by glutamate receptors and calcineurin. J. Neurosci. 18:9835–44 [Google Scholar]
  37. Hasbani MJ, Schlief ML, Fisher DA, Goldberg MP. 37.  2001. Dendritic spines lost during glutamate receptor activation reemerge at original sites of synaptic contact. J. Neurosci. 21:2393–403 [Google Scholar]
  38. Tolino M, Köhrmann M, Kiebler MA. 38.  2012. RNA-binding proteins involved in RNA localization and their implications in neuronal diseases. Eur. J. Neurosci. 35:1818–36 [Google Scholar]
  39. Campbell JN, Register D, Churn SB. 39.  2011. Traumatic brain injury causes an FK506-sensitive loss and an overgrowth of dendritic spines in rat forebrain. J. Neurotrauma 29:201–17 [Google Scholar]
  40. Tong L, Prieto GA, Kramár EA, Smith ED, Cribbs DH. 40.  et al. 2012. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase. J. Neurosci. 32:17714–24 [Google Scholar]
  41. Centonze D, Muzio L, Rossi S, Cavasinni F. Chiara V. 41. , De et al. 2009. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J. Neurosci. 29:3442–52 [Google Scholar]
  42. Fiala JC, Spacek J, Harris KM. 42.  2002. Dendritic spine pathology: cause or consequence of neurological disorders?. Brain Res. Rev. 39:29–54 [Google Scholar]
  43. Peters A, Sethares C, Moss MB. 43.  1998. The effects of aging on layer 1 in area 46 of prefrontal cortex in the rhesus monkey. Cereb. Cortex 8:671–84 [Google Scholar]
  44. Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB. 44.  et al. 2012. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 123:825–39 [Google Scholar]
  45. Filser S, Ovsepian SV, Masana M, Blazquez-Llorca L, Brandt Elvang A. 45.  et al. 2014. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol. Psychiatry 77:729–39 [Google Scholar]
  46. Nhan H, Chiang K, Koo E. 46.  2015. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol. 129:1–19 [Google Scholar]
  47. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D. 47.  et al. 2003. APP Processing and synaptic function. Neuron 37:925–37 [Google Scholar]
  48. Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR. 48.  et al. 2005. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron 48:913–22 [Google Scholar]
  49. Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E. 49.  et al. 2006. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry 45:12393–99 [Google Scholar]
  50. DeMattos RB, Lu J, Tang Y, Racke MM, DeLong CA. 50.  et al. 2012. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron 76:908–20 [Google Scholar]
  51. Brendel M, Jaworska A, Griessinger E, Rotzer C, Burgold S. 51.  et al. 2015. Cross-sectional comparison of small animal [18F]-florbetaben amyloid-PET between transgenic AD mouse models. PLOS ONE 10:e0116678 [Google Scholar]
  52. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A. 52.  et al. 2012. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367:795–804 [Google Scholar]
  53. Bittner T, Burgold S, Dorostkar M, Fuhrmann M, Wegenast-Braun B. 53.  et al. 2012. Amyloid plaque formation precedes dendritic spine loss. Acta Neuropathol. 124:797–807 [Google Scholar]
  54. Dorostkar MM, Burgold S, Filser S, Barghorn S, Schmidt B. 54.  et al. 2014. Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model. Brain 137:3319–26 [Google Scholar]
  55. Burgold S, Filser S, Dorostkar MM, Schmidt B, Herms J. 55.  2014. In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques. Acta Neuropathol. Commun. 2:30 [Google Scholar]
  56. Burgold S, Bittner T, Dorostkar M, Kieser D, Fuhrmann M. 56.  et al. 2010. In vivo multiphoton imaging reveals gradual growth of newborn amyloid plaques over weeks. Acta Neuropathol. 121:327–35 [Google Scholar]
  57. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML. 57.  et al. 2009. Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. PNAS 106:4012–17 [Google Scholar]
  58. Wu H-Y, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A. 58.  et al. 2010. Amyloid β induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J. Neurosci. 30:2636–49 [Google Scholar]
  59. Kirkwood CM, Ciuchta J, Ikonomovic MD, Fish KN, Abrahamson EE. 59.  et al. 2013. Dendritic spine density, morphology, and fibrillar actin content surrounding amyloid-β plaques in a mouse model of amyloid-β deposition. J. Neuropathol. Exp. Neurol. 72:791–800 [Google Scholar]
  60. Bittner T, Fuhrmann M, Burgold S, Ochs SM, Hoffmann N. 60.  et al. 2010. Multiple events lead to dendritic spine loss in triple transgenic Alzheimer's disease mice. PLOS ONE 5:e15477 [Google Scholar]
  61. Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA. 61.  et al. 2009. Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 132:402–16 [Google Scholar]
  62. Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N. 62.  et al. 2014. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron 84:1023–33 [Google Scholar]
  63. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold K-H. 63.  et al. 2008. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science 321:1686–89 [Google Scholar]
  64. Chakroborty S, Stutzmann G. 64.  2011. Early calcium dysregulation in Alzheimer's disease: setting the stage for synaptic dysfunction. Sci. China Life Sci. 54:752–62 [Google Scholar]
  65. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu H-Y, Hyman BT, Bacskai BJ. 65.  2008. Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59:214–25 [Google Scholar]
  66. Garcia-Marin V, Blazquez-Llorca L, Rodriguez J-R, Boluda S, Muntane G. 66.  et al. 2009. Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques. Front. Neuroanat. 3:28 [Google Scholar]
  67. Benilova I, Karran E, De Strooper B. 67.  2012. The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes. Nat. Neurosci. 15:349–57 [Google Scholar]
  68. Resenberger UK, Harmeier A, Woerner AC, Goodman JL, Müller V. 68.  et al. 2011. The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication. EMBO J. 30:2057–70 [Google Scholar]
  69. Benilova I, De Strooper B. 69.  2013. Promiscuous Alzheimer's amyloid: yet another partner. Science 341:1354–55 [Google Scholar]
  70. Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ. 70.  et al. 2013. Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann. Neurol. 73:104–19 [Google Scholar]
  71. Koffie RM, Hashimoto T, Tai H-C, Kay KR, Serrano-Pozo A. 71.  et al. 2012. Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135:2155–68 [Google Scholar]
  72. Fowler SW, Chiang ACA, Savjani RR, Larson ME, Sherman MA. 72.  et al. 2014. Genetic modulation of soluble Aβ rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease. J. Neurosci. 34:7871–85 [Google Scholar]
  73. Larson ME, Lesné SE. 73.  2012. Soluble Aβ oligomer production and toxicity. J. Neurochem. 120:125–39 [Google Scholar]
  74. Zempel H, Mandelkow EM. 74.  2012. Linking amyloid-β and tau: amyloid-β induced synaptic dysfunction via local wreckage of the neuronal cytoskeleton. Neurodegener. Dis. 10:64–72 [Google Scholar]
  75. Lashuel HA, Lansbury PT Jr. 75.  2006. Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?. Q. Rev. Biophys. 39:167–201 [Google Scholar]
  76. Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M. 76.  et al. 2012. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15:1227–35 [Google Scholar]
  77. Boehm J. 77.  2013. A ‘danse macabre’: tau and Fyn in STEP with amyloid beta to facilitate induction of synaptic depression and excitotoxicity. Eur. J. Neurosci. 37:1925–30 [Google Scholar]
  78. Mori C, Spooner ET, Wisniewski KE, Wisniewski TM, Yamaguchi H. 78.  et al. 2002. Intraneuronal Aβ42 accumulation in Down syndrome brain. Amyloid 9:88–102 [Google Scholar]
  79. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M. 79.  et al. 2000. Intraneuronal Aβ42 accumulation in human brain. Am. J. Pathol. 156:15–20 [Google Scholar]
  80. Nunomura A, Tamaoki T, Tanaka K, Motohashi N, Nakamura M. 80.  et al. 2010. Intraneuronal amyloid β accumulation and oxidative damage to nucleic acids in Alzheimer disease. Neurobiol. Dis. 37:731–37 [Google Scholar]
  81. Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK. 81.  2013. Accumulation of intraneuronal β-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses. PLOS ONE 8:e51965 [Google Scholar]
  82. Blair JA, Siedlak SL, Wolfram JA, Nunomura A, Castellani RJ. 82.  et al. 2014. Accumulation of intraneuronal amyloid-β is common in normal brain. Curr. Alzheimer Res. 11:317–24 [Google Scholar]
  83. Shie F-S, LeBoeur RC, Jin L-W. 83.  2003. Early intraneuronal Aβ deposition in the hippocampus of APP transgenic mice. NeuroReport 14:123–29 [Google Scholar]
  84. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA. 84.  et al. 2002. Intraneuronal Alzheimer Aβ42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161:1869–79 [Google Scholar]
  85. Umeda T, Tomiyama T, Kitajima E, Idomoto T, Nomura S. 85.  et al. 2012. Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice. Life Sci. 91:1169–76 [Google Scholar]
  86. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E. 86.  et al. 2009. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction. PNAS 106:20021–26 [Google Scholar]
  87. Zhao W, Dumanis SB, Tamboli IY, Rodriguez GA, Jo LaDu M. 87.  et al. 2014. Human APOE genotype affects intraneuronal Aβ1–42 accumulation in a lentiviral gene transfer model. Hum. Mol. Genet. 23:1365–75 [Google Scholar]
  88. Mahley RW, Weisgraber KH, Huang Y. 88.  2006. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. PNAS 103:5644–51 [Google Scholar]
  89. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. 89.  1996. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer's disease. J. Neurosci. 16:5795–811 [Google Scholar]
  90. Oakley H, Cole SL, Logan S, Maus E, Shao P. 90.  et al. 2006. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26:10129–40 [Google Scholar]
  91. Moon M, Hong H-S, Nam DW, Baik SH, Song H. 91.  et al. 2012. Intracellular amyloid-β accumulation in calcium-binding protein-deficient neurons leads to amyloid-β plaque formation in animal model of Alzheimer's disease. J. Alzheimer's Dis. 29:615–28 [Google Scholar]
  92. Christensen DZ, Huettenrauch M, Mitkovski M, Pradier L, Wirths O. 92.  2014. Axonal degeneration in an Alzheimer mouse model is PS1 gene dose dependent and linked to intraneuronal Aβ accumulation. Front. Aging Neurosci. 6:139 [Google Scholar]
  93. Eimer W, Vassar R. 93.  2013. Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation. Mol. Neurodegener. 8:2 [Google Scholar]
  94. Villar AJ, Belichenko PV, Gillespie AM, Kozy HM, Mobley WC, Epstein CJ. 94.  2005. Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(1716)65Dn and mouse chromosome 12. Mamm. Genome 16:79–90 [Google Scholar]
  95. Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ. 95.  et al. 2004. Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J. Comp. Neurol. 480:281–98 [Google Scholar]
  96. Zou C, Montagna E, Shi Y, Peters F, Blazquez-Llorca L. 95a.  et al. 2015. Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer's disease. Acta Neuropathol. 129:6909–20 [Google Scholar]
  97. Gouras GK, Willén K, Faideau M. 96.  2014. The inside-out amyloid hypothesis and synapse pathology in Alzheimer's disease. Neurodegener. Dis. 13:142–46 [Google Scholar]
  98. Auffret A, Gautheron V, Repici M, Kraftsik R, Mount HT. 97.  et al. 2009. Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease. J. Neurosci. 29:10144–52 [Google Scholar]
  99. Jung CKE, Fuhrmann M, Honarnejad K, Van Leuven F, Herms J. 98.  2011. Role of presenilin1 in structural plasticity of cortical dendritic spines in vivo. J. Neurochem. 119:1064–73 [Google Scholar]
  100. Sun S, Zhang H, Liu J, Popugaeva E, Xu NJ. 99.  et al. 2014. Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron 82:79–93 [Google Scholar]
  101. Wang Y, Greig NH, Yu QS, Mattson MP. 100.  2009. Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices. Neurobiol. Aging 30:1061–68 [Google Scholar]
  102. Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N. 101.  et al. 2001. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J. Biol. Chem. 276:11539–44 [Google Scholar]
  103. Zaman SH, Parent A, Laskey A, Lee MK, Borchelt DR. 102.  et al. 2000. Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine. Neurobiol. Dis. 7:54–63 [Google Scholar]
  104. Barrow PA, Empson RM, Gladwell SJ, Anderson CM, Killick R. 103.  et al. 2000. Functional phenotype in transgenic mice expressing mutant human presenilin-1. Neurobiol. Dis. 7:119–26 [Google Scholar]
  105. Dewachter I, Ris L, Croes S, Borghgraef P, Devijver H. 104.  et al. 2008. Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1. Neurobiol. Aging 29:639–52 [Google Scholar]
  106. Parent A, Linden DJ, Sisodia SS, Borchelt DR. 105.  1999. Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1. Neurobiol. Dis. 6:56–62 [Google Scholar]
  107. Xia D, Watanabe H, Wu B, Lee SH, Li Y. 106.  et al. 2015. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron 85:967–81 [Google Scholar]
  108. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF. 107.  et al. 2006. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126:981–93 [Google Scholar]
  109. Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I. 108.  2010. Role of presenilins in neuronal calcium homeostasis. J. Neurosci. 30:8566–80 [Google Scholar]
  110. Cheung KH, Shineman D, Muller M, Cardenas C, Mei L. 109.  et al. 2008. Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58:871–83 [Google Scholar]
  111. Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T. 110.  et al. 2010. Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Sci. Signal. 3:ra22 [Google Scholar]
  112. Smith IF, Hitt B, Green KN, Oddo S, LaFerla FM. 111.  2005. Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease. J. Neurochem. 94:1711–18 [Google Scholar]
  113. Chakroborty S, Goussakov I, Miller MB, Stutzmann GE. 112.  2009. Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J. Neurosci. 29:9458–70 [Google Scholar]
  114. Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. 113.  2006. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J. Neurosci. 26:5180–89 [Google Scholar]
  115. Honarnejad K, Jung CKE, Lammich S, Arzberger T, Kretzschmar H, Herms J. 114.  2013. Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease. J. Cell. Mol. Med. 17:293–302 [Google Scholar]
  116. Nagaishi M, Arai M, Osawa T, Yokoo H, Hirato J. 115.  et al. 2011. An immunohistochemical finding in glioneuronal lesions associated with epilepsy: the appearance of nestin-positive, CD34-positive and tau-accumulating cells. Neuropathology 31:468–75 [Google Scholar]
  117. Zheng P, Shultz SR, Hovens CM, Velakoulis D, Jones NC, O'Brien TJ. 116.  2014. Hyperphosphorylated tau is implicated in acquired epilepsy and neuropsychiatric comorbidities. Mol. Neurobiol. 49:1532–39 [Google Scholar]
  118. Geddes JF, Vowles GH, Nicoll JA, Revesz T. 117.  1999. Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol. 98:171–78 [Google Scholar]
  119. Sen A, Thom M, Martinian L, Harding B, Cross JH. 118.  et al. 2007. Pathological tau tangles localize to focal cortical dysplasia in older patients. Epilepsia 48:1447–54 [Google Scholar]
  120. Suzuki K, Parker CC, Pentchev PG, Katz D, Ghetti B. 119.  et al. 1995. Neurofibrillary tangles in Niemann–Pick disease type C. Acta Neuropathol. 89:227–38 [Google Scholar]
  121. Love S, Bridges LR, Case CP. 120.  1995. Neurofibrillary tangles in Niemann–Pick disease type C. Brain 118:119–29 [Google Scholar]
  122. Leroy K, Ando K, Laporte V, Dedecker R, Suain V. 121.  et al. 2012. Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am. J. Pathol. 181:1928–40 [Google Scholar]
  123. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J. 122.  et al. 2011. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J. Neurosci. 31:700–11 [Google Scholar]
  124. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH. 123.  et al. 2007. Reducing endogenous tau ameliorates amyloid ß-induced deficits in an Alzheimer's disease mouse model. Science 316:750–54 [Google Scholar]
  125. Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG. 124.  2004. Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am. J. Pathol. 165:1643–52 [Google Scholar]
  126. Hoffmann N, Dorostkar M, Blumenstock S, Goedert M, Herms J. 125.  2013. Impaired plasticity of cortical dendritic spines in P301S tau transgenic mice. Acta Neuropathol. Commun. 1:82 [Google Scholar]
  127. Nizzari M, Barbieri F, Gentile MT, Passarella D, Caorsi C. 126.  et al. 2012. Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau. J. Alzheimer's Dis. 29:211–27 [Google Scholar]
  128. Blum D, Herrera F, Francelle L, Mendes T, Basquin M. 127.  et al. 2014. Mutant huntingtin alters Tau phosphorylation and subcellular distribution. Hum. Mol. Genet. 24:76–85 [Google Scholar]
  129. Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H. 128.  et al. 2013. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 32:2920–37 [Google Scholar]
  130. Liu C, Gotz J. 129.  2013. Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLOS ONE 8:e84849 [Google Scholar]
  131. Rosenmann H. 130.  2014. Asparagine endopeptidase cleaves tau and promotes neurodegeneration. Nat. Med. 20:1236–38 [Google Scholar]
  132. Zhang Z, Song M, Liu X, Kang SS, Kwon I-S. 131.  et al. 2014. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat. Med. 20:1254–62 [Google Scholar]
  133. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H. 132.  et al. 2014. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–88 [Google Scholar]
  134. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S. 133.  et al. 2013. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. PNAS 110:9535–40 [Google Scholar]
  135. de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz David H. 134.  et al. 2012. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685–97 [Google Scholar]
  136. Dujardin S, Lecolle K, Caillierez R, Begard S, Zommer N. 135.  et al. 2014. Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Acta Neuropathol. Commun. 2:14 [Google Scholar]
  137. Liu L, Drouet V, Wu JW, Witter MP, Small SA. 136.  et al. 2012. Trans-synaptic spread of tau pathology in vivo. PLOS ONE 7:e31302 [Google Scholar]
  138. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. 137.  2006. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112:389–404 [Google Scholar]
  139. SantaCruz K, Lewis J, Spires T, Paulson J, Kotilinek L. 138.  et al. 2005. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–81 [Google Scholar]
  140. Kuchibhotla KV, Wegmann S, Kopeikina KJ, Hawkes J, Rudinskiy N. 139.  et al. 2014. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. PNAS 111:510–14 [Google Scholar]
  141. Polydoro M, Dzhala VI, Pooler AM, Nicholls SB, McKinney AP. 140.  et al. 2014. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer's disease model. Acta Neuropathol. 127:257–70 [Google Scholar]
  142. Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N. 141.  et al. 2007. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–51 [Google Scholar]
  143. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA. 142.  et al. 2010. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–81 [Google Scholar]
  144. Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK. 143.  2010. Co-occurrence of Alzheimer's disease β-amyloid and tau pathologies at synapses. Neurobiol. Aging 31:1145–52 [Google Scholar]
  145. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A. 144.  et al. 2010. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142:387–97 [Google Scholar]
  146. Harris JA, Koyama A, Maeda S, Ho K, Devidze N. 145.  et al. 2012. Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLOS ONE 7:e45881 [Google Scholar]
  147. Tai H-C, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. 146.  2012. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181:1426–35 [Google Scholar]
  148. Tai H-C, Wang B, Serrano-Pozo A, Frosch M, Spires-Jones T, Hyman B. 147.  2014. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer's disease. Acta Neuropathol. Commun. 2:146 [Google Scholar]
  149. Mondragón-Rodríguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M. 148.  et al. 2012. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J. Biol. Chem. 287:32040–53 [Google Scholar]
  150. Rocher AB, Crimins JL, Amatrudo JM, Kinson MS, Todd-Brown MA. 149.  et al. 2010. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp. Neurol. 223:385–93 [Google Scholar]
  151. Liu X, Erikson C, Brun A. 150.  1996. Cortical synaptic changes and gliosis in normal aging, Alzheimer's disease and frontal lobe degeneration. Dementia 7:128–34 [Google Scholar]
  152. Mocanu M-M, Nissen A, Eckermann K, Khlistunova I, Biernat J. 151.  et al. 2008. The potential for β-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous tau in inducible mouse models of tauopathy. J. Neurosci. 28:737–48 [Google Scholar]
  153. Schindowski K, Bretteville A, Leroy K, Begard S, Brion JP. 152.  et al. 2006. Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am. J. Pathol. 169:599–616 [Google Scholar]
  154. Aguzzi A, Heikenwalder M, Polymenidou M. 153.  2007. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8:552–61 [Google Scholar]
  155. Jeffrey M, McGovern G, Siso S, Gonzalez L. 154.  2011. Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease. Acta Neuropathol. 121:113–34 [Google Scholar]
  156. Jeffrey M, Halliday WG, Bell J, Johnston AR, MacLeod NK. 155.  et al. 2000. Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus. Neuropathol. Appl. Neurobiol. 26:41–54 [Google Scholar]
  157. Fuhrmann M, Mitteregger G, Kretzschmar H, Herms J. 156.  2007. Dendritic pathology in prion disease starts at the synaptic spine. J. Neurosci. 27:6224–33 [Google Scholar]
  158. Siskova Z, Reynolds RA, O'Connor V, Perry VH. 157.  2013. Brain region specific pre-synaptic and post-synaptic degeneration are early components of neuropathology in prion disease. PLOS ONE 8:e55004 [Google Scholar]
  159. Gray BC, Siskova Z, Perry VH, O'Connor V. 158.  2009. Selective presynaptic degeneration in the synaptopathy associated with ME7-induced hippocampal pathology. Neurobiol. Dis. 35:63–74 [Google Scholar]
  160. Jamieson E, Jeffrey M, Ironside JW, Fraser JR. 159.  2001. Apoptosis and dendritic dysfunction precede prion protein accumulation in 87V scrapie. NeuroReport 12:2147–53 [Google Scholar]
  161. Chiesa R, Drisaldi B, Quaglio E, Migheli A, Piccardo P. 160.  et al. 2000. Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation. PNAS 97:5574–79 [Google Scholar]
  162. Jeffrey M, Goodsir C, McGovern G, Barmada SJ, Medrano AZ, Harris DA. 161.  2009. Prion protein with an insertional mutation accumulates on axonal and dendritic plasmalemma and is associated with distinctive ultrastructural changes. Am. J. Pathol. 175:1208–17 [Google Scholar]
  163. Zhou M, Ottenberg G, Sferrazza GF, Lasmezas CI. 162.  2012. Highly neurotoxic monomeric α-helical prion protein. PNAS 109:3113–18 [Google Scholar]
  164. Simoneau S, Rezaei H, Sales N, Kaiser-Schulz G, Lefebvre-Roque M. 163.  et al. 2007. In vitro and in vivo neurotoxicity of prion protein oligomers. PLOS Pathog. 3:e125 [Google Scholar]
  165. Novitskaya V, Bocharova OV, Bronstein I, Baskakov IV. 164.  2006. Amyloid fibrils of mammalian prion protein are highly toxic to cultured cells and primary neurons. J. Biol. Chem. 281:13828–36 [Google Scholar]
  166. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N. 165.  et al. 2012. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485:507–11 [Google Scholar]
  167. Zaja-Milatovic S, Milatovic D, Schantz AM, Zhang J, Montine KS. 166.  et al. 2005. Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease. Neurology 64:545–47 [Google Scholar]
  168. McNeill TH, Brown SA, Rafols JA, Shoulson I. 167.  1988. Atrophy of medium spiny I striatal dendrites in advanced Parkinson's disease. Brain Res. 455:148–52 [Google Scholar]
  169. Neuner J, Ovsepian SV, Dorostkar M, Filser S, Gupta A. 168.  et al. 2014. Pathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb. Nat. Commun. 5:3915 [Google Scholar]
  170. Diogenes MJ, Dias RB, Rombo DM, Vicente Miranda H, Maiolino F. 169.  et al. 2012. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J. Neurosci. 32:11750–62 [Google Scholar]
  171. Hüls S, Hogen T, Vassallo N, Danzer KM, Hengerer B. 170.  et al. 2011. AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced α-synuclein oligomers. J. Neurochem. 117:868–78 [Google Scholar]
  172. Collingridge GL, Isaac JT, Wang YT. 171.  2004. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5:952–62 [Google Scholar]
  173. Bliss TV, Collingridge GL. 172.  1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39 [Google Scholar]
  174. Pozo K, Goda Y. 173.  2010. Unraveling mechanisms of homeostatic synaptic plasticity. Neuron 66:337–51 [Google Scholar]
  175. Kramer ML, Schulz-Schaeffer WJ. 174.  2007. Presynaptic α-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J. Neurosci. 27:1405–10 [Google Scholar]
  176. Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. 175.  2010. A pathologic cascade leading to synaptic dysfunction in α-synuclein-induced neurodegeneration. J. Neurosci. 30:8083–95 [Google Scholar]
  177. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B. 176.  et al. 2010. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66–79 [Google Scholar]
  178. Soper JH, Roy S, Stieber A, Lee E, Wilson RB. 177.  et al. 2008. α-Synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae. Mol. Biol. Cell 19:1093–103 [Google Scholar]
  179. Gitler D, Cheng Q, Greengard P, Augustine GJ. 178.  2008. Synapsin IIa controls the reserve pool of glutamatergic synaptic vesicles. J. Neurosci. 28:10835–43 [Google Scholar]
  180. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. 179.  2005. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123:383–96 [Google Scholar]
  181. Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P. 180.  et al. 2006. α-Synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J. Neurosci. 26:11915–22 [Google Scholar]
  182. Ferrante RJ, Kowall NW, Richardson EP Jr. 181.  1991. Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J. Neurosci. 11:3877–87 [Google Scholar]
  183. Graveland GA, Williams RS, DiFiglia M. 182.  1985. Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science 227:770–73 [Google Scholar]
  184. Sotrel A, Williams RS, Kaufmann WE, Myers RH. 183.  1993. Evidence for neuronal degeneration and dendritic plasticity in cortical pyramidal neurons of Huntington's disease: a quantitative Golgi study. Neurology 43:2088–96 [Google Scholar]
  185. Spires TL, Grote HE, Garry S, Cordery PM, Van Dellen A. 184.  et al. 2004. Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice. Eur. J. Neurosci. 19:2799–807 [Google Scholar]
  186. Nithianantharajah J, Barkus C, Vijiaratnam N, Clement O, Hannan AJ. 185.  2009. Modeling brain reserve: experience-dependent neuronal plasticity in healthy and Huntington's disease transgenic mice. Am. J. Geriatr. Psychiatry 17:196–209 [Google Scholar]
  187. Heck N, Betuing S, Vanhoutte P, Caboche J. 186.  2012. A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington's disease. Brain Struct. Funct. 217:421–34 [Google Scholar]
  188. Murmu RP, Li W, Holtmaat A, Li JY. 187.  2013. Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington's disease. J. Neurosci. 33:12997–3009 [Google Scholar]
  189. Li JY, Conforti L. 188.  2013. Axonopathy in Huntington's disease. Exp. Neurol. 246:62–71 [Google Scholar]
  190. Ratnavalli E, Brayne C, Dawson K, Hodges JR. 189.  2002. The prevalence of frontotemporal dementia. Neurology 58:1615–21 [Google Scholar]
  191. Rohrer JD, Isaacs AM, Mizielinska S, Mead S, Lashley T. 190.  et al. 2015. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol. 14:291–301 [Google Scholar]
  192. Gorrie GH, Fecto F, Radzicki D, Weiss C, Shi Y. 191.  et al. 2014. Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. PNAS 111:14524–29 [Google Scholar]
  193. Thal DR, Rub U, Orantes M, Braak H. 192.  2002. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–800 [Google Scholar]
  194. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. 193.  2011. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70:960–69 [Google Scholar]
  195. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB. 194.  et al. 2011. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3:89ra57 [Google Scholar]
  196. Berg L, McKeel DW Jr, Miller JP, Storandt M, Rubin EH. 195.  et al. 1998. Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch. Neurol. 55:326–35 [Google Scholar]
  197. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E. 196.  et al. 2003. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 60:1495–500 [Google Scholar]
  198. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D. 197.  et al. 1998. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–54 [Google Scholar]
  199. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D. 198.  et al. 2011. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 122:111–13 [Google Scholar]
  200. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC. 199.  et al. 2006. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–33 [Google Scholar]
  201. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IRA. 200.  2009. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–31 [Google Scholar]
  202. Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z. 201.  et al. 2008. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum. Mol. Genet. 17:3631–42 [Google Scholar]
  203. Prinz M, Heikenwalder M, Junt T, Schwarz P, Glatzel M. 202.  et al. 2003. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425:957–62 [Google Scholar]
  204. Head MW, Ironside JW. 203.  2012. Review: Creutzfeldt–Jakob disease: prion protein type, disease phenotype and agent strain. Neuropathol. Appl. Neurobiol. 38:296–310 [Google Scholar]
  205. Parchi P, Strammiello R, Giese A, Kretzschmar H. 204.  2011. Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol. 121:91–112 [Google Scholar]
  206. De Rosa P, Marini ES, Gelmetti V, Valente EM. 205.  2015. Candidate genes for Parkinson disease: lessons from pathogenesis. Clin. Chim. Acta 449:68–76 [Google Scholar]
  207. Reiner A, Dragatsis I, Dietrich P. 206.  2011. Genetics and neuropathology of Huntington's disease. Int. Rev. Neurobiol. 98:325–72 [Google Scholar]
  208. Ingre C, Roos PM, Piehl F, Kamel F, Fang F. 207.  2015. Risk factors for amyotrophic lateral sclerosis. Clin. Epidemiol. 7:181–93 [Google Scholar]
  209. Lattante S, Ciura S, Rouleau GA, Kabashi E. 208.  2015. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet. 31:263–73 [Google Scholar]
  210. Mori K, Weng SM, Arzberger T, May S, Rentzsch K. 209.  et al. 2013. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–38 [Google Scholar]

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