Role of Apolipoproteins and α-Synuclein in Parkinson’s Disease

Acciarri A, Masullo C, Bizzarro A (2006) ApoE epsilon2-epsilon4 genotype is a possible risk factor for primary progressive aphasia. Ann Neurol 59:436–437 Agosta F, Vossel KA, Miller BL, Migliaccio R, Bonasera SJ, Filippi M, Boxer AL, Karydas A, Possin KL, Gorno-Tempini ML (2009) Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc Natl Acad Sci USA 106:2018–2022 Alonso A, Huang X, Mosley TH, Heiss G, Chen H (2015) Heart rate variability and the risk of Parkinson disease: the atherosclerosis risk in communities study. Ann Neurol 77:877–883 Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJ, Cooper JM (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 42:360–367 Alves da Costa C, Ancolio K, Checler F (2000) Wild-type but not Parkinson’s disease-related ala-53 → Thr mutant α-synuclein protects neuronal cells from apoptotic stimuli. Biol Chem 275:24065–24069 Amouyel P, Vidal O, Launay JM, Laplanche JL (1994) The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. The French Research Group on Epidemiology of Human Spongiform Encephalopathies. Lancet 344: 1315–1318 Bales KR (2010) Brain lipid metabolism, apolipoprotein E and the pathophysiology of Alzheimer’s disease. Neuropharmacology 59:295–302 Bernis ME, Babila JT, Breid S, Wüsten KA, Wüllner U, Tamgüney G (2015) Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein. Acta Neuropathol Commun 3:75 Bisaglia M, Greggio E, Maric D, Miller DW, Cookson MR, Bubacco L (2010) Alpha-synuclein overexpression increases dopamine toxicity in BE2-M17 cells. BMC Neurosci 11:41 Blair, C. K., Folsom, A. R., Knopman, D. S., Bray, M. S., Mosley, T. H., Boerwinkle, E., Atherosclerosis risk in communities (ARIC) study investigators. APOE genotype and cognitive decline in a middle-aged cohort Neurology 64: 268–276, 2005. Blázquez L, Otaegui D, Sáenz A, Paisán-Ruiz C, Emparanza JI, Ruiz-Martinez J, Moreno F, Martí-Massó JF, López de Munain A (2006) Apolipoprotein E epsilon4 allele in familial and sporadic Parkinson’s disease. Neurosci Lett 406:235–239 Braak H, Del Tredici K, Rüb 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 Braesch-Andersen S, Beckman L, Paulie S, Kumagai-Braesch M (2014) ApoD mediates binding of HDL to LDL and to growing T24 carcinoma. PLoS One 9:e115180 Brewer HB Jr, Fairwell T, Kay L, Meng M, Ronan R, Law S, Light JA (1983) Human plasma proapoA-I: isolation and amino-terminal sequence. Biochem Biophys Res Commun 113:626–632 Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, Michaelson DM, Korczyn AD (2001) APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 56:312–316 Chen G, Paka L, Kako Y, Singhal P, Duan W, Pillarisetti S (2001) A protective role for kidney apolipoprotein E: regulation of mesangial cell proliferation and matrix expansion. J Biol Chem 276:49142–49147 Chen H-K, Ji Z-S, Dodson SE, Miranda RD, Rosenblum CI, Reynolds IJ, Freedman SB, Weisgraber KH, Huang Y, Mahley RW (2011) Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer’s disease. J Biol Chem 286:5215–5221 Cohen RM, Small C, Lalonde F, Friz J, Sunderland T (2001) Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology 57:2223–2228 Colzato LS, Van Den Wildenberg WP, Van Wouwe NC, Pannebakker MM, Hommel B (2009) Dopamine and inhibitory action control: evidence from spontaneous eye blink rates. Exp Brain Res 196:467–474 Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alphasynuclein adduct. Science 294:1346–1349 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 Dal Forno G, Carson KA, Brookmeyer R, Troncoso J, Kawas CH, Brandt J (2002) APOE genotype and survival in men and women with Alzheimer’s disease. Neurology 58:1045–1050 de Knijff P, van den Maagdenberg AMJM, Frants RR, Havekes LM (1994) Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. Hum Mutat 4:178–194 de Silva HV, Harmony JA, Stuart WD, Gil CM, Robbins J (1990) Apolipoprotein J: structure and tissue distribution. Biochemistry 29:5380–5389 Duvoisin RC (1996) Recent advances in the genetics of Parkinson’s disease. Adv Neurol 69:33–40 Elliott DA, Weickert CS, Garner B (2010) Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clin Lipidol 51:555–573 Emamzadeh FN (2016) Alpha-synuclein structure, functions, and interactions. J Res Med Sci 21:29 Emamzadeh FN, Aojula H, McHugh PC, Allsop D (2016) Effects of different isoforms of apoE on aggregation of the α-synuclein protein implicated in Parkinson’s disease. Neurosci Lett 618:146–151 Factor SA, Steenland NK, Higgins DS, Molho ES, Kay DM, Montimurro J, Rosen AR, Zabetian CP, Payami H (2011) Postural instability/gait disturbance in Parkinson’s disease has distinct subtypes: an exploratory analysis. J Neurol Neurosurg Psychiatry 82:564–568 Fantini J, Carlus D, Yahi N (2011) The fusogenic tilted peptide (67-78) of α-synuclein is a cholesterol binding domain. Biochim Biophys Acta 1808:2343–2351 Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC (2004) Impact of APOE in mild cognitive impairment. Neurology 63:1898–1901 Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB (2012) A large study reveals no association between APOE and Parkinson’s disease. Neurobiol Dis 46:389–392 Gao N, Li YH, Li X, Yu S, Fu GL, Chen B (2007) Effect of alpha-synuclein on the promoter activity of tyrosine hydroxylase gene. Neurosci Bull 23:53–57 Gelissen IC, Hochgrebe T, Wilson MR, Easterbrook-Smith SB, Jessup W, Dean RT, Brown AJ (1998) Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function? Biochem J 331:231–237 Ghebranious N, Ivacic L, Mallum J, Dokken C (2005) Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology. Nucleic Acids Res 33:e149 Ghebremedhin E, Schultz C, Thal DR, Rub U, Ohm TG, Braak E (2001) Gender and age modify the association between APOE and AD-related neuropathology. Neurology 56:1696–1701 Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 104:18754–18759 Gregorio ML, Pinhel MA, Sado CL, Longo GS, Oliveira FN, Amorim GS, Nakazone MA, Florim GM, Mazeti CM, Martins DP, Tognola WA, Brandão AC, Júnior SP, de Godoy MF, Souza DR (2013) Impact of genetic variants of apolipoprotein E on lipid profile in patients with Parkinson’s disease. Biomed Res Int 2013:641515. doi:10.1155/2013/641515 Harada R, Kobayashi N, Kim J, Nakamura C, Han SW, Ikebukuro K, Sode K (2009) The effect of amino acid substitution in the imperfect repeat sequences of α-synuclein on fibrillation. Biochim Biophys 1792:998–1003 Hayashi H, Campenot RB, Vance DE, Vance JE (2007) Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1. J Neurosci 27:1933–1941 Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J (2010) DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 133:713–726 Huang X, Chen PC, Poole C (2004) APOEε2 allele associated with higher prevalence of sporadic Parkinson disease. Neurology 62:2198–2202 Iwata A (2001) Maruyama1, M., Kanazawa, I., Nukina, N. α -Synuclein affects the MAPK pathway and accelerates cell death. Biol Chem 276:45320–45329 Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376 Jensen P, Nielsen M, Jakes R, Dotti C, Goedert M (1998) Binding of α-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. Biol Chem 273:26292–26294 Kamino K, Tanaka T, Kida T, Ohkochi M, Tanii H, Kudo T, Takeda M (2002) The role of lipid metabolism in Alzheimer’s disease. Nihon Shinkei Seishin Yakurigaku Zasshi 22:103–110 Kandimalla RJ, Prabhakar S, Binukumar BK, Wani WY, Gupta N, Sharma DR, Sunkaria A, Grover VK, Bhardwaj N, Jain K, Gill KD (2011) Apo-Eε4 allele in conjunction with Aβ42 and tau in CSF: biomarker for Alzheimer’s disease. Curr Alzheimer Res 8:187–196 Kantarci OH, Hebrink DD, Achenbach SJ, Pittock SJ, Altintas A, Schaefer-Klein JL, Atkinson EJ, de Andrade M, McMurray CT, Rodriguez M, Weinshenker BG (2004) Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 62:811–814 Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J (1994) Apolipoprotein E polymorphism in Japanese patients with Alzheimer’s disease or vascular dementia. J Neurol Neurosurg Psychiatry 57:1414–1416 Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL (1999) Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 36:108–111 Koob AO, Ubhi K, Paulsson JF, Kelly J, Rockenstein E, Mante M, Adame A, Masliah E (2010) Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies. Exp Neurol 221:267–274 Koutsis G, Panas M, Giogkaraki E et al (2007) APOE epsilon4 is associated with impaired verbal learning in patients with MS. Neurology 68:546–549 Lambert JC, Harris JM, Mann D, Lemmon H, Coates J, Cumming A, St-Clair D, Lendon C (2001) Are the estrogen receptors involved in Alzheimer’s disease? Neurosci Lett 306:193–197 Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, Savalle M, Nemani V, Chaudhry FA, Edwards RH, Stefanis L, Sulzer D (2006) Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci 26:11915–11922 Lees A, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066 Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395:451–452 Lesage S, Brice A (2009) Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 18:48–59 Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L, Dawson TM, Jäkälä P, Hartmann T, Price DL, Lee MK (2005) Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci USA 8:2162–2167 Lindersson E, Beedholm R, Hojrup P, Moos T, Gai W, Hendil KB, Jensen PH (2004) Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279:12924–12934 Liu C-C, Kanekiyo T, Xu H, Bu G (2012) Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nat Rev Neurol 9:106–118 Lotharius J, Barg S, Wiekop P, Lundberg C, Raymon HK, Brundin P (2002) Effect of mutant α-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 277:38884–38894 Lou HMSE, Alerte TN, Wang J, Wu J, Peng XM, Hong CS, Friedrich EE, Mader SA, Pedersen CJ, Marcus BS, McCormack AL, Di Monte DA, Daubner SC, Perez RG (2010) Serine 129 phosphorylation reduces α–synuclein’s ability to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. J Biol Chem 285:17648–11766 Lucotte G, Turpin JC, Landais P (1994) Apolipoprotein E-epsilon 4 allele doses in late-onset Alzheimer’s disease. Ann Neurol 36:681–682 Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Pathological α-Synuclein transmission initiates Parkinson-like neurodegeneration in non-transgenic mice. Science 16:949–953 Magrinelli F, Picelli A, Tocco P, Federico A, Roncari L, Smania N, Zanette G, Tamburin S (2016) Pathophysiology of motor dysfunction in Parkinson’s disease as the rationale for drug treatment and rehabilitation. Parkinsons Dis 2016:9832839. doi:10.1155/2016/9832839 Martinez J, Moeller I, Erdjument-Bromage H, Tempst P, Lauring B (2003) Parkinson’s disease associated α synuclein is a calmodulin substrate. Biol Chem 278:17379–17387 McLean PJ, Kawamata H, Ribich S, Hyman BT (2000) Membrane association and protein conformation of α-synuclein in intact neurons. Effect of Parkinson’s disease-linked mutations. Biol Chem 275:8812–8816 Miners JS, Clarke P, Love S (2017) Clusterin levels are increased in Alzheimer’s disease and influence the regional distribution of Aβ. Brain Pathol 27:305–313 Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67:122–131 Moussa CE, Wersinger C, Rusnak M, Tomita Y, Sidhu A (2004) Abnormal migration of human wild-type α-synuclein upon gel electrophoresis. Neurosci Lett 371:239–243 Multhammer M, Michels A, Zintl M, Mendoza MC, Klünemann HH (2014) A large ApoE ε4/ε4 homozygous cohort reveals no association with Parkinson’s disease. Acta Neurol Belg 114:25–31 Navarro A, Mendez E, Diaz C, del Valle E, Martinez-Pinilla E, Ordonez C, Tolivia J (2013) Lifelong expression of apolipoprotein D in the human brainstem: correlation with reduced age-related neurodegeneration. PLoS One 8:e 77852. doi:10.1371/journal.pone.0077852 Ordoñez C, Navarro A, Perez C, Astudillo A, Martínez E, Tolivia J (2006) Apolipoprotein D expression in substantia nigra of Parkinson disease. Histol Histopathol 21:361–366 Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T α -Synuclein mutation increases iron-dependent aggregation and toxicity. Neuroscience 20:6048–6054 Parsian A, Racette B, Goldsmith LJ, Perlmutter JS (2002) Parkinson’s disease and apolipoprotein E: possible association with dementia but not age at onset. Genomics 79:458–4561 Payami H, Zareparsi S, Montee KR, Sexton GJ, Kaye JA, Bird TD, Yu CE, Wijsman EM, Heston LL, Litt M, Schellenberg GD (1996) Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 58:803–811 Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG (2005) Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci 118:3523–3530 Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22:3090–3099 Phillips M, Apolipoprotein C (2014) E isoforms and lipoprotein metabolism. IUBMB Life 66:616–623 Pirskanen M, Hiltunen M, Mannermaa A, Helisalmi S, Lehtovirta M, Hänninen T, Soininen H (2005) Eur J Hum Genet 13:1000–1006 Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinisto L, Halonen P, Kontula K (1995) Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med 333:1242–1247 Ponsford J, McLaren A, Schönberger M, Burke R, Rudzki D, Olver J, Ponsford M (2011) The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. J Neurotrauma 28:1683–1692 Puglielli L, Tanzi RE, Kovacs DM (2003) Alzheimer’s disease: the cholesterol connection. Nat Neurosci 6:345–351 Qiang JK, Wong YC, Siderowf A, Hurtig HI, Xie SX, Lee VM, Trojanowski JQ, Yearout DB, Leverenz J, Montine TJ, Stern M, Mendick S, Jennings D, Zabetian C, Marek K, Chen-Plotkin AS (2013) Plasma apolipoprotein A1 as a biomarker for Parkinson disease. Ann Neurol 74:119–127 Raichlen DA, Alexander GE (2014) Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci 37:247–255 Rajagopalan S, Andersen JK (2001) Α synuclein aggregation: is it the toxic gain of function responsible for neurodegeneration in Parkinson’s disease? Mech Ageing Dev 122:1499–1510 Rassart E, Bediriana A, Do Carmoa S, Guinarda O, Siroisa J, Terrissea L, Milneb R Apolipoprotein D (2000) Biochim Biophys Acta 1482: 185–198 Royston MC, Mann D, Pickering-Brown S, Owen F, Perry R, Raghavan R, Khin-Nu C, Tyrer S, Day K, Crook R (1994) Apolipoprotein E epsilon 2 allele promotes longevity and protects patients with Down’s syndrome from dementia. Neuroreport 5:2583–2585 Ruipérez V, Darios F, Davletov B (2010) Alpha-synuclein, lipids and Parkinson’s disease. Prog Lipid Res 49:420–428 Salawu FK, Danburam A, Olokoba AB (2010) Non-motor symptoms of Parkinson’s disease: diagnosis and management. Niger J Med 19:126–131 Sanan DA, Weisgraber KH, Russel SJ, Mahley RW, Huang D, Saunders A, Schmechel D, Wisniewksi T, Frangione B, Roses B (1994) Apolipoprotein E associates with β amyloid peptide of Alzheimer’s disease to form novel monofibrils. J Clin Invest 94:860–869 Sasaki K, Doh-ura K, Wakisaka Y, Iwaki T (2002) Clusterin/apolipoprotein J is associated with cortical Lewy bodies: immunohistochemical study in cases with alpha-synucleinopathies. Acta Neuropathol 104:225–230 Schapira AH (1995) Nuclear and mitochondrial genetics in Parkinson’s disease. Med Genet 32:411–414 Shults CW (2006) Lewy bodies. Proc Natl Acad Sci USA 103:1661–1668 Silva F, Rodriguez-Revenga L, Madrigal I, Alvarez-Mora MI, Oliva R, Mila M (2013) High apolipoprotein E4 allele frequency in FXTAS patients. Genet Med 15:639–642 Sousa VL, Bellani S, Giannandrea M, Yousuf M, Valtorta F, Meldolesi J, Chieregatti E (2009) α-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Mol Biol Cell 20:3725–3739 Stefanis L, Larsen KE, Rideout HJ, Sulzer D, Greene LA (2001) Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21:9549–9560 Steiner JA, Angot E, Brundin P (2011) A deadly spread: cellular mechanisms of α-synuclein transfer. Cell Death Differ 18:1425–1433 Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:8098–8102 Swanson CR, Berlyand Y, Xie SX, Alcalay RN, Chahine LM, Chen-Plotkin AS (2015) Plasma apolipoprotein A1 associates with age at onset and motor severity in early Parkinson’s disease patients. Mov Disord 30:1648–1656 Tabrizi S, Orth M, Wilkinson JM, Taanman JW, Warner TT, Cooper JM, Schapira AHV (2000) Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity. Hum Mol Genet 9:2683–2689 Talbot C, Lendon C, Craddock N, Shears S, Morris JC, Goate A (1994) Protection against Alzheimer’s disease with apoEε2. Lancet 343:1432–1433 Tamam Y, Tasdemir N, Yalman M, Tamam B (2011) Association of apolipoprotein E genotypes with prognosis in multiple sclerosis. Eur Rev Med Pharmacol Sci 15:1122–1130 Tang MX, Maestre G, Tsai WY, Liu XH, Feng L, Chung WY, Chun M, Schofield P, Stern Y, Tycko B, Mayeux R (1996) Effect of age, ethnicity, and head injury on the association between APOE genotypes and Alzheimer’s disease. Ann NY Acad Sci 802:6–15 Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, John V, Rao RV, Bredesen DE (2013) Neuroprotective sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci 110:18303–18308 Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62:1984–1989 Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP (2013) APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70:223–228 Ulusoy A, Febbraro F, Jensen PH, Kirik D, Romero-Ramos M (2012) Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathology. Eur J Neurosci 32:409–422 Van Laar AD, Jain S (2004) Non-motor symptoms of Parkinson disease: update on the diagnosis and treatment. Neurologist 10:185–194 van Maarschalkerweerd A, Vetri V, Vestergaard B (2015) Cholesterol facilitates interactions between α-synuclein oligomers and charge-neutral membranes. FEBS Lett 589:2661–2667 Varkey J, Isas JM, Mizuno N, Jensen MB, Bhatia VK, Jao CC, Petrlova J, Voss JC, Stamou DG, Steven AC, Langen R (2010) Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J Biol Chem 285:32486–32493 Venda LL, Cragg SJ, Buchman VL, Wade-Martins R (2010) α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci 33:559–568 Vitali C, Wellington CL, Calabresi L (2014) HDL and cholesterol handling in the brain. Cardiovasc Res 103:405–413 Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283:23542–23556 Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, Yu HY, Wang SJ, Liu HC (2000) Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 54:2061–2066 Wang ES, Sun Y, Guo JG, Gao X, Hu JW, Zhou L, Hu J, Jiang CC (2010) Tetranectin and apolipoprotein A-I in cerebrospinal fluid as potential biomarkers for Parkinson’s disease. Acta Neurol Scand 122:350–359 Wider C, Ross OA, Nishioka K, Heckman MG, Vilariño-Güell C, Jasinska-Myga B, Erketin-Taner N, Rademakers R, Graff-Radford NR, Mash DC, Papapetropoulos S, Duara R, Uchikado H, Wszolek ZK, Farrer MJ, Dickson DW (2012) An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer’s and Lewy body pathology. J Neurol Neurosurg Psychiatry 83:424–429 Wilhelmus MM, Bol JG, Van Haastert ES, Rozemuller AJ, Bu G, Drukarch B, Hoozemans JJ (2011) Apolipoprotein E and LRP1 Increase Early in Parkinson’s Disease Pathogenesis. Am J Pathol 179:2152–2156 Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA (2002) Participation in cognitively stimulating activities and risk of incident Alzheimer disease. J Am Med Assoc 287:742–748 Wong P, Taillefer D, Lakins J, Pineault J, Chader G, Tenniswood M (1994) Molecular characterization of human TRPM-2/clusterin, a gene associated with sperm maturation, apoptosis and neurodegeneration. Eur J Biochem 221:917–925 Yavich L, Oksman M, Tanila H, Kerokoski P, Hiltunen M, van Groen T, Puoliväli J, Männistö PT, García-Horsman A, MacDonald E, Beyreuther K, Hartmann T, Jäkälä P (2005) Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human alpha-synuclein. Neurobiol Dis 20:303–313 Yshii LM, Denadai-Souza A, Vasconcelos AR, Avellar MC, Scavone C (2015) Suppression of MAPK attenuates neuronal cell death induced by activated glia-conditioned medium in alpha-synuclein overexpressing SH-SY5Y cells. J Neuroinflammation 12:193 Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uéda K, Chan P (2007) Extensive nuclear localization of α-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145:539–555 Zareparsi S, Camicioli R, Sexton G, Bird T, Swanson P, Kaye J, Nutt J, Payami H (2002) Age at onset of Parkinson disease and apolipoprotein E genotypes. Am J Med Genet 107:156–161