Animal Models of Neurodegenerative Diseases 85 still essential elements in the laborious attempts to determine the etiology of a given disease, understand its progression, and the relationship between the observed clin- ical phenotypes and the histological features or hallmarks of the disease. A growing need is now acknowledged to combine-join-converge research programs between clinicians and basic researchers who should reach for a consensual language. This should help extrapolate findings obtained in animal models to the human pathol- ogy and identify and apply means that will prevent or delay, if not cure, the disease. Acknowledgments GP wishes to thank AIRMA (Association Internationale pour la Recherche sur la Maladie d’Alzheimer), the LECMA (Ligue Européenne Contre la Maladie d’Alzheimer) and The Poitiers University Hospital. Work on animal models of neurodegenerative disorders in the group of MJ and AG is financed by the Fondation de France, Institut pour la Recherche sur la Moelle Epinière and the CNRS interdisciplinary program “Aging”. References Abbott A (2004) Laboratory animals: the Renaissance rat. Nature 428:464–466 Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lack- ing alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252 Aigner TG, Mishkin M (1986) The effects of physostigmine and scopolamine on recognition memory in monkeys. Behav Neural Biol 45:81–87 Aigner TG, Mitchell SJ, Aggleton JP, DeLong MR, Struble RG, Price DL, Wenk GL, Mishkin M (1987) Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert. Psychopharmacology (Berl) 92: 292–300 Aigner TG, Mitchell SJ, Aggleton JP, DeLong MR, Struble RG, Price DL, Wenk GL, Pettigrew KD, Mishkin M (1991) Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques. Exp Brain Res 86:18–26 Albin RL (1995) Selective neurodegeneration in Huntington’s disease. Ann Neurol 38: 835–836 Alexi T, Hughes PE, Faull RL, Williams CE (1998) 3-Nitropropionic acid’s lethal triplet: cooperative pathways of neurodegeneration. Neuroreport 9:R57–R64 Andra K, Abramowski D, Duke M, Probst A, Wiederhold KH, Burki K, Goedert M, Sommer B, Staufenbiel M (1996) Expression of APP in transgenic mice: a comparison of neuron-specific promoters. Neurobiol Aging 17:183–190 Bader V, Ran Zhu X, Lubbert H, Stichel CC (2005) Expression of DJ-1 in the adult mouse CNS. Brain Res 1041:102–111 Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, Fishman CE, DeLong CA, Piccardo P, Petegnief V, Ghetti B, Paul SM (1999) Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 96:15233–15238 Barrier L, Ingrand S, Damjanac M, Rioux Bilan A, Hugon J, Page G (2007) Genotype- related changes of ganglioside composition in brain regions of transgenic mouse models of Alzheimer’s disease. Neurobiol Aging 28:1863–1872 Barrier L, Ingrand S, Fauconneau B, Page G (2008) Gender-dependent accumulation of ceramides in the cerebral cortex of the APP(SL)/PS1Ki mouse model of Alzheimer’s disease. Neurobiol Aging 86 I. Ghorayeb et al. Bartus RT, Dean RL, Fleming DL (1979) Aging in the rhesus monkey: effects on visual discrimination learning and reversal learning. J Gerontol 34:209–219 Bartus RT, Fleming D, Johnson HR (1978) Aging in the rhesus monkey: debilitating effects on short-term memory. J Gerontol 33:858–871 Bartus RT, Johnson HR (1976) Short-term memory in the rhesus monkey: disruption from the anti-cholinergic scopolamine. Pharmacol Biochem Behav 5:39–46 Bayer TA, Wirths O (2008) Review on the APP/PS1KI mouse model: intraneuronal Abeta accumu- lation triggers axonopathy, neuron loss and working memory impairment. Genes Brain Behav 7(Suppl 1):6–11 Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334 Benarroch EE (2002) New findings on the neuropathology of multiple system atrophy. Auton Neurosci 96:59–62 Bertram L, Tanzi RE (2008) Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9:768–778 Bezard E, Boraud T, Bioulac B, Gross CE (1999) Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms. Eur J Neurosci 11:2167–2170 Bezard E, Brotchie JM, Gross C E (2001) Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2:577–588 Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu SW, Savitt JM, Waldvogel HJ, Faull RL, Emson PC, Torp R, Ottersen OP, Dawson TM, Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 60:557–569 Blanchard V, Moussaoui S, Czech C, Touchet N, Bonici B, Planche M, Canton T, Jedidi I, Gohin M, Wirths O, Bayer TA, Langui D, Duyckaerts C, Tremp G, Pradier L (2003) Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 184:247–263 Boncristiano S, Calhoun ME, Kelly PH, Pfeifer M, Bondolfi L, Stalder M, Phinney AL, Abramowski D, Sturchler-Pierrat C, Enz A, Sommer B, Staufenbiel M, Jucker M (2002) Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 22:3234–3243 Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259 Botcherby M (2002) Harvesting the mouse genome. Comp Funct Genomics 3:319–324 Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24: 197–211 Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Dee Fish J, Wyss-Coray T, Buttini M, Mucke L, Mahley RW, Huang Y (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24:2527–2534 Breese GR, Traylor TD (1971) Depletion of brain noradrenaline and dopamine by 6- hydroxydopamine. Br J Pharmacol 42:88–99 Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88: 1337–1342 Brouillet E, Conde F, Beal MF, Hantraye P (1999) Replicating Huntington’s disease phenotype in experimental animals. Prog Neurobiol 59:427–468 Brouillet E, Guyot MC, Mittoux V, Altairac S, Conde F, Palfi S, Hantraye P (1998) Partial inhibi- tion of brain succinate dehydrogenase by 3-nitropropionic acid is sufficient to initiate striatal degeneration in rat. J Neurochem 70:794–805 Brouillet E, Hantraye P (1995) Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates. Curr Opin Neurol 8:469–473 Animal Models of Neurodegenerative Diseases 87 Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R medi- ates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338 Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80:4546–4550 Cai H, Shim H, Lai C, Xie C, Lin X, Yang WJ, Chandran J (2008) ALS2/alsin knockout mice and motor neuron diseases. Neurodegener Dis 5:359–366 Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–14093 Carter DB, Dunn E, McKinley DD, Stratman NC, Boyle TP, Kuiper SL, Oostveen JA, Weaver RJ, Boller JA, Gurney ME (2001) Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. Ann Neurol 50:468–475 Carter RJ, L ione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19:3248–3257 Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L (2004) Massive CA1/2 neuronal loss with intraneu- ronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300 Cauchi RJ, van den Heuvel M (2006) The fly as a model for neurodegenerative diseases: is it worth the jump? Neurodegener Dis 3:338–356 Cetin F, Dincer S (2007) The effect of intrahippocampal beta amyloid (1–42) peptide injection on oxidant and antioxidant status in rat brain. Ann N Y Acad Sci 1100:510–517 Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, Carvey PM, Ling Z, Kang UJ, Zhuang X (2005) Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 280:21418–21426 Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D (2001) Early-onset amyloid depo- sition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276:21562–21570 Chou SM, Wang HS, Taniguchi A, Bucala R (1998) Advanced glycation endproducts in neurofil- ament conglomeration of motoneurons in familial and sporadic amyotrophic lateral sclerosis. Mol Med 4:324–332 Christensen DZ, Bayer TA, Wirths O (2008a) Intracellular Abeta triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer’s disease. Neurobiol Aging Christensen DZ, Kraus SL, Flohr A, Cotel MC, Wirths O, Bayer TA (2008b) Transient intraneu- ronal A beta rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice. Acta Neuropathol 116:647–655 Chrysostome V, Tison F, Yekhlef F, Sourgen C, Baldi I, Dartigues JF (2004) Epidemiology of multiple system atrophy: a prevalence and pilot risk factor study in Aquitaine, France. Neuroepidemiology 23:201–208 Cicchetti F, Gould PV, Parent A (1996) Sparing of striatal neurons coexpressing calretinin and substance P (NK1) receptor in Huntington’s disease. Brain Res 730:232–237 Cleveland DW (1999) From Charcot to SOD1: mechanisms of selective motor neuron death in ALS. Neuron 24:515–520 88 I. Ghorayeb et al. Cookson MR (2005) The biochemistry of Parkinson’s disease. Annu Rev Biochem 74:29–52 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923 Cotel MC, Bayer TA, Wirths O (2008) Age-dependent loss of dentate gyrus granule cells in APP/PS1KI mice. Brain Res 1222:207–213 Cozzolino M, Ferri A, Carri MT (2008) Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications. Antioxid Redox Signal 10:405–443 Damjanac M, Rioux Bilan A, Barrier L, Pontcharraud R, Anne C, Hugon J, Page G (2007) Fluoro-Jade B staining as useful tool to identify activated microglia and astrocytes in a mouse transgenic model of Alzheimer’s disease. Brain Res 1128:40–49 Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R (2002) Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 99:14524–14529 Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39: 889–909 Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548 Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, Ferrante RJ (2003) Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem 85:1359–1367 DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993 Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathol- ogy: similarities and differences. Acta Neuropathol 115:5–38 Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, Muro A, Baralle F, Li H, Duff K, Szyf M, Cuello AC (2004) Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J Alzheimers Dis 6:209–219 Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma- secretase activity. Nat Cell Biol 5:486–488 Eikelenboom P, Veerhuis R, Scheper W, Rozemuller AJ, van Gool WA, Hoozemans JJ (2006) The significance of neuroinflammation in understanding Alzheimer’s disease. J Neural Transm 113:1685–1695 Elbaz A, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, Schaid DJ, Rocca WA (2002) Risk tables for parkinsonism and Parkinson’s disease. J Clin Epidemiol 55:25–31 Faber PW, Alter JR, MacDonald ME, Hart AC (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci USA 96: 179–184 Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14 Fearnley JM, Lees AJ (1990) Striatonigral degeneration. A clinicopathological study. Brain 113(Pt 6):1823–1842 Fernagut PO, Diguet E, Bioulac B, Tison F (2004) MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice: reference to striatonigral degeneration. Exp Neurol 185:47–62 Ferrante RJ, Kowall NW, Cipolloni PB, Storey E, Beal MF (1993) Excitotoxin lesions in primates as a model for Huntington’s disease: histopathologic and neurochemical characterization. Exp Neurol 119:46–71 Figueredo-Cardenas G, Harris CL, Anderson KD, Reiner A (1998) Relative resistance of stri- atal neurons containing calbindin or parvalbumin to quinolinic acid-mediated excitotoxicity compared to other striatal neuron types. Exp Neuro 149:356–372 Animal Models of Neurodegenerative Diseases 89 Fitten LJ, Perryman K, Tachiki K, Kling A (1988) Oral tacrine administration in middle-aged monkeys: effects on discrimination learning. Neurobiol Aging 9:221–224 Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, Scott RW, Howland DS (2007) A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. Neurobiol Aging Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D, Bader M, Winblad B, Benedikz E (2007) A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation. Biochem Biophys Res Commun 358:777–782 Foster AC, C ollins JF, Schwarcz R (1983) On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds. Neuropharmacology 22:1331–1342 Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM (2003) Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J Neurosci 23: 7889–7896 Fu AL, Dong ZH, Sun MJ (2006) Protective effect of N-acetyl-L-cysteine on amyloid beta-peptide- induced learning and memory deficits in mice. Brain Res 1109:201–206 Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51:296–301 Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524 Gearing M, Rebeck GW, Hyman BT, Tigges J, Mirra SS (1994) Neuropathology and apolipopro- tein E profile of aged chimpanzees: implications for Alzheimer disease. Proc Natl Acad Sci USA 91:9382–9386 Gearing M, Tigges J, Mori H, Mirra SS (1997) beta-Amyloid (A beta) deposition in the brains of aged orangutans. Neurobiol Aging 18:139–146 Ghorayeb I, Fernagut PO, Aubert I, Bezard E, Poewe W, Wenning GK, Tison F (2000) Toward a primate model of L-dopa-unresponsive parkinsonism mimicking striatonigral degeneration. Mov Disord 15:531–536 Ghorayeb I, Fernagut PO, Hervier L, Labattu B, Bioulac B, Tison F (2002) A ‘single toxin-double lesion’ rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis. Neuroscience 115:533–546 Ghorayeb I, Puschban Z, Fernagut PO, Scherfler C, Rouland R, Wenning GK, Tison F (2001) Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early- stage striatonigral degeneration. Exp Neurol 167:133–147 Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, Van Deerlin VM (2006) Biochemical and pathological characterization of Lrrk2. Ann Neurol 59:315–322 Giovanni A, Sieber BA, Heikkila RE, Sonsalla PK (1991) Correlation between the neostriatal content of the 1-methyl-4-phenylpyridinium species and dopaminergic neurotoxicity follow- ing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to several strains of mice. J Pharmacol Exp Ther 257:691–697 Giraldo P, Montoliu L (2001) Size matters: use of YACs, BACs and PACs in transgenic animals. Transgenic Res 10:83–103 Glinka YY, Youdim MB (1995) Inhibition of mitochondrial complexes I and IV by 6- hydroxydopamine. Eur J Pharmacol 292:329–332 Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8: 159–168 Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 278:43628–43635 90 I. Ghorayeb et al. Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J (2005) Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45:489–496 Goldstein DS, Li ST, Holmes C, Bankiewicz K (2003) Sympathetic innervation in the 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson’s disease. J Pharmacol Exp Ther 306:855–860 Gonzalo-Ruiz A, Perez JL, Sanz JM, Geula C, Arevalo J (2006) Effects of lipids and aging on the neurotoxicity and neuronal loss caused by intracerebral injections of the amyloid-beta peptide in the rat. Exp Neurol 197:41–55 Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495 Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544 Gotz J, Probst A, Spillantini MG, Schafer T, Jakes R, Burki K, Goedert M (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14:1304–1313 Gotz J, Streffer JR, David D, Schild A, Hoerndli F, Pennanen L, Kurosinski P, Chen F (2004) Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy. Mol Psychiatry 9:664–683 Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr., Hardiman O (2006) ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet 38:411–413 Gros-Louis F, Lariviere R, Gowing G, Laurent S, Camu W, Bouchard JP, Meininger V, Rouleau GA, Julien JP (2004) A frameshift deletion in peripherin gene a ssociated with amyotrophic lateral sclerosis. J Biol Chem 279:45951–45956 Guegan C, Vila M, Rosoklija G, Hays AP, Przedborski S (2001) Recruitment of the mitochondrial- dependent apoptotic pathway in amyotrophic lateral sclerosis. J Neurosci 21:6569–6576 Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante RJ, Hersch SM, Li XJ (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19:2522–2534 Guyot MC, Palfi S, Stutzmann JM, Maziere M, Hantraye P, Brouillet E (1997) Riluzole pro- tects from motor deficits and striatal degeneration produced by systemic 3-nitropropionic acid intoxication in rats. Neuroscience 81:141–149 Hall GF, Yao J, Lee G (1997) Human tau becomes phosphorylated and forms filamentous deposits when overexpressed in lamprey central neurons in situ. Proc Natl Acad Sci USA 94:4733–4738 Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388 Harper PS (1992) The epidemiology of Huntington’s disease. Hum Genet 89:365–376 Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H, Yoshino H, Asahina M, Kobayashi S, Hassin-Baer S, Lu CS, Ng AR, Rosales RL, Shimizu N, Toda T, Mizuno Y, Hattori N (2004) Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 56:424–427 Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl- 1,2,5,6-tetrahydropyridine in mice. Science 224:1451–1453 Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55:221–235 Hensley K, Floyd RA (2002) Reactive oxygen species and protein oxidation in aging: a look back, a look ahead. Arch Biochem Biophys 397:377–383 Higashi S, Biskup S, West AB, Trinkaus D, Dawson VL, Faull RL, Waldvogel HJ, Arai H, Dawson TM, Moore DJ, Emson PC (2007a) Localization of Parkinson’s disease-associated LRRK2 in normal and pathological human brain. Brain Res 1155:208–219 Animal Models of Neurodegenerative Diseases 91 Higashi S, Moore DJ, Colebrooke RE, Biskup S, Dawson VL, Arai H, Dawson TM, Emson PC (2007b) Expression and localization of Parkinson’s disease-associated leucine-rich repeat kinase 2 in the mouse brain. J Neurochem 100:368–381 Higgins GA, Jacobsen H (2003) Transgenic mouse models of Alzheimer’s disease: phenotype and application. Behav Pharmacol 14:419–438 Hirsch EC, Hoglinger G, Rousselet E, Breidert T, Parain K, Feger J, Ruberg M, Prigent A, Cohen- Salmon C, Launay JM (2003) Animal models of Parkinson’s disease in rodents induced by toxins: an update. J Neural Transm Suppl 65:89–100 Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D (1999) Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet 29:177–185 Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4: 97–100 Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223 Holtzman DM (2004) In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. J Mol Neurosci 23:247–254 Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99:1604–1609 Hyun DH, Lee M, Halliwell B, Jenner P (2003) Proteasomal inhibition causes the formation of pro- tein aggregates containing a wide range of proteins, including nitrated proteins. J Neurochem 86:363–373 Ichitani Y, Okamura H, Matsumoto Y, Nagatsu I, Ibata Y (1991) Degeneration of the nigral dopamine neurons after 6-hydroxydopamine injection into the rat striatum. Brain R es 549: 350–353 Irle E, Markowitsch HJ (1987) Basal forebrain-lesioned monkeys are severely impaired in tasks of association and recognition memory. Ann Neurol 22:735–743 Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM (2001) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 158:555–562 Jaber M, Robinson SW, Missale C, Caron MG (1996) Dopamine receptors and brain function. Neuropharmacology 35:1503–1519 Janus C, Westaway D (2001) Transgenic mouse models of Alzheimer’s disease. Physiol Behav 73:873–886 Jarvis MF, Wagner GC (1985) Age-dependent effects of 1-methyl-4-phenyl-1,2,5,6- tetrahydropyridine (MPTP). Neuropharmacology 24:581–583 Jenner P (2003) The MPTP-treated primate as a model of motor complications in PD: primate model of motor complications. Neurology 61:S4–S11 Jeon BS, Jackson-Lewis V, Burke RE (1995) 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4:131–137 Jin K, LaFevre-Bernt M, Sun Y, Chen S, Gafni J, Crippen D, Logvinova A, Ross CA, Greenberg DA, Ellerby LM (2005) FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 102:18189–18194 Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18:1979–1986 92 I. Ghorayeb et al. Jonsson PA, Ernhill K, Andersen PM, Bergemalm D, Brannstrom T, Gredal O, Nilsson P, Marklund SL (2004) Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis. Brain 127:73–88 Jonsson PA, Graffmo KS, Andersen PM, Brannstrom T, Lindberg M, Oliveberg M, Marklund SL (2006) Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models. Brain 129:451–464 Julien JP, Kriz J (2006) Transgenic mouse models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:1013–1024 Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendro- cytes. EMBO Rep 3:583–588 Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P (2008) Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 7:812–826 Kato S (2008) Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Acta Neuropathol 115:97–114 Kazemi-Esfarjani P, Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287:1837–1840 Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW (2005) Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128:2786–2796 Kim GW, Chan PH (2001) Oxidative stress and neuronal DNA fragmentation mediate age- dependent vulnerability to the mitochondrial toxin, 3-nitropropionic acid, in the mouse striatum. Neurobiol Dis 8:114–126 Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215–5220 Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A (2003) Nigrostriatal alpha- synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA 100:2884–2889 Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608 Lai ZC, Moss MB, Killiany RJ, Rosene DL, Herndon JG (1995) Executive system dysfunction in the aged monkey: spatial and object reversal learning. Neurobiol Aging 16:947–954 Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980 Langston JW, Forno LS, Rebert CS, Irwin I (1984a) Selective nigral toxicity after systemic admin- istration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res 292:390–394 Langston JW, Irwin I, Langston EB, Forno LS (1984b) 1-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 48:87–92 Lantos PL (1998) The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 57:1099–1111 Laviola G, Hannan AJ, Macri S, Solinas M, Jaber M (2008) Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis 31: 159–168 Animal Models of Neurodegenerative Diseases 93 Lee SB, Kim W, Lee S, Chung J (2007) Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun 358:534–539 Leung CL, He CZ, Kaufmann P, Chin SS, Naini A, Liem RK, Mitsumoto H, Hays AP (2004) A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. Brain Pathol 14:290–296 Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofib- rillary degeneration in transgenic mice expressing mutant tau and APP. Science 293: 1487–1491 Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405 Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20:589–602 Link CD (2005) Invertebrate models of Alzheimer’s disease. Genes Brain Behav 4:147–156 Liu J, Lillo C, Jonsson PA, Vande Velde C, Ward CM, Miller TM, Subramaniam JR, Rothstein JD, Marklund S, Andersen PM, Brannstrom T, Gredal O, Wong PC, Williams DS, Cleveland DW (2004) Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43:5–17 Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K (2008a) A transgenic rat that develops Alzheimer’s disease- like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis 31:46–57 Liu Y, Yoo MJ, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue ME, Lee MK (2008b) Amyloid pathology is associated with progressive monoamin- ergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease. J Neurosci 28:13805–13814 Logroscino G, Traynor BJ, Hardiman O, Chio A, Couratier P, Mitchell JD, Swingler RJ, Beghi E (2008) Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry 79:6–11 Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991) 3-Nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18:492–498 Luo Y, Bolon B, Damore MA, Fitzpatrick D, Liu H, Zhang J, Yan Q, Vassar R, Citron M (2003) BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol Dis 14:81–88 Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506 Manning-Bog AB, Caudle WM, Perez XA, Reaney SH, Paletzki R, Isla MZ, Chou VP, McCormack AL, Miller GW, Langston JW, Gerfen CR, Dimonte DA (2007) Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter. Neurobiol Dis 27:141–150 Martin LJ, Sisodia SS, Koo EH, Cork LC, Dellovade TL, Weidemann A, Beyreuther K, Masters C, Price DL (1991) Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci USA 88:1461–1465 Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, Roses AD (1995) Neurodegeneration in the central nervous system of apoE-deficient mice. Exp Neurol 136:107–122 Mattson MP (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 77:1081–1132 Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered beta- amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193 94 I. Ghorayeb et al. McGeer EG, McGeer PL (1976) Duplication of biochemical changes of Huntington’s chorea by intrastriatal injections of glutamic and kainic acids. Nature 263:517–519 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944 Menalled LB, Chesselet MF (2002) Mouse models of Huntington’s disease. Trends Pharmacol Sci 23:32–39 Meredith GE, Kang UJ (2006) Behavioral models of Parkinson’s disease in rodents: a new look at an old problem. Mov Disord 21:1595–1606 Millecamps S, Robertson J, Lariviere R, Mallet J, Julien JP (2006) Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin. J Neurochem 98:926–938 Mizuno Y, Sone N, Saitoh T (1987) Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on activities of the enzymes in the electron transport system in mouse brain. J Neurochem 48:1787–1793 Moore TL, Killiany RJ, Herndon JG, Rosene DL, Moss MB (2006) Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol Aging 27:1484–1493 Moore DJ, Zhang L, Troncoso J, Lee MK, Hattori N, Mizuno Y, Dawson TM, Dawson VL (2005) Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum Mol Genet 14:71–84 Muyllaert D, Terwel D, Kremer A, Sennvik K, Borghgraef P, Devijver H, Dewachter I, Van Leuven F (2008) Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. Am J Pathol 172: 470–485 Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622 Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochon- dria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6- tetrahydropyridine. Life Sci 36:2503–2508 Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421 Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41:27–33 Okamoto K, Mizuno Y, Fujita Y (2008) Bunina bodies in amyotrophic lateral sclerosis. Neuropathology 28:109–115 Ouary S, Bizat N, Altairac S, Menetrat H, Mittoux V, Conde F, Hantraye P, Brouillet E (2000) Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies. Neuroscience 97:521–530 Page G, Rioux Bilan A, Ingrand S, Lafay-Chebassier C, Pain S, Perault Pochat MC, Bouras C, Bayer T, Hugon J (2006) Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer’s disease. Neuroscience 139:1343–1354 Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44: 595–600 Palfi S, Brouillet E, Jarraya B, Bloch J, Jan C, Shin M, Conde F, Li XJ, Aebischer P, Hantraye P, Deglon N (2007) Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates. Mol Ther 15:1444–1451 . Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993 Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease. study in Aquitaine, France. Neuroepidemiology 23:201–208 Cicchetti F, Gould PV, Parent A (1996) Sparing of striatal neurons coexpressing calretinin and substance P (NK1) receptor in Huntington’s disease. . of Huntington’s disease. Proc Natl Acad Sci USA 102:18189–18194 Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter.