Abstract
Alzheimer’s disease (AD) is a highly heritable disease (with heritability up to 76 %) with a complex genetic profile of susceptibility, among which large genome-wide association studies (GWASs) pointed to the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a susceptibility locus for late-onset Alzheimer’s disease (LOAD) incidence. Here, we summarize the known functions of PICALM and discuss its genetic polymorphisms and their potential physiological effects associated with LOAD. Compelling data indicated that PICALM affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy, synaptic dysfunction, disorganized lipid metabolism, immune disorder, and disrupted iron homeostasis. Finally, given the potential involvement of PICALM in facilitating AD occurrence in multiple ways, it might be possible that targeting PICALM might provide promising and novel avenues for AD therapy.
Similar content being viewed by others
References
Avramopoulos D (2009) Genetics of Alzheimer’s disease: recent advances. Genome Med 1(3):34. doi:10.1186/gm34
Jiang T, Yu JT, Tian Y, Tan L (2013) Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 10(8):852–867
Meng XF, Yu JT, Wang HF, Tan MS, Wang C, Tan CC, Tan L (2014) Midlife vascular risk factors and the risk of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimer’s Dis JAD. doi:10.3233/JAD-140954
Xu W, Yu JT, Tan MS, Tan L (2014) Cognitive reserve and Alzheimer’s disease. Mol Neurobiol. doi:10.1007/s12035-014-8720-y
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706. doi:10.1038/349704a0
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534):754–760. doi:10.1038/375754a0
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269(5226):973–977
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90(5):1977–1981
Yu JT, Tan L, Hardy J (2014) Apolipoprotein e in Alzheimer’s disease: an update. Annu Rev Neurosci 37:79–100. doi:10.1146/annurev-neuro-071013-014300
Ashford JW, Mortimer JA (2002) Non-familial Alzheimer’s disease is mainly due to genetic factors. J Alzheimers Dis 4(3):169–177
Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 338(8):506–511. doi:10.1056/NEJM199802193380804
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753. doi:10.1038/nature08494
Yu JT, Song JH, Ma T, Zhang W, Yu NN, Xuan SY, Tan L (2011) Genetic association of PICALM polymorphisms with Alzheimer’s disease in Han Chinese. J Neurol Sci 300(1–2):78–80. doi:10.1016/j.jns.2010.09.027
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093. doi:10.1038/ng.440
Szule JA, Jarvis SE, Hibbert JE, Spafford JD, Braun JE, Zamponi GW, Wessel GM, Coorssen JR (2003) Calcium-triggered membrane fusion proceeds independently of specific presynaptic proteins. J Biol Chem 278(27):24251–24254. doi:10.1074/jbc.C300197200
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, Destefano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Hollingworth P, Ramirez A, Hanon O, Fitzpatrick AL, Buxbaum JD, Campion D, Crane PK, Baldwin C, Becker T, Gudnason V, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Moron FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fievet N, Huentelman MJ, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuinness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossu P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer’s Disease Initiative, Environmental Risk Genetic in Alzheimer’s Disease, Alzheimer’s Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannfelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O’Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltunen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nothen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458. doi:10.1038/ng.2802
Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O’Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, Group C-AT (2007) Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med 357(14):1382–1392. doi:10.1056/NEJMoa066583
Morgan K, Carrasquillo MM (2013) Genetic variants in Alzheimer’s disease. Springer Science & Business, New York
Morgan EE, Woods SP, Letendre SL, Franklin DR, Bloss C, Goate A, Heaton RK, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Ellis RJ, Abramson I, Gamst A, Fennema-Notestine C, Smith DM, Grant I, Vaida F, Clifford DB, Group CHATER (2013) Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders. J Neurovirol 19(2):150–156. doi:10.1007/s13365-013-0152-3
Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT (2001) Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science 291(5506):1051–1055. doi:10.1126/science.291.5506.1051
Yao PJ, Zhang P, Mattson MP, Furukawa K (2003) Heterogeneity of endocytic proteins: distribution of clathrin adaptor proteins in neurons and glia. Neuroscience 121(1):25–37
Tebar F, Bohlander SK, Sorkin A (1999) Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol Biol Cell 10(8):2687–2702
Bushlin I, Petralia RS, Wu F, Harel A, Mughal MR, Mattson MP, Yao PJ (2008) Clathrin assembly protein AP180 and CALM differentially control axogenesis and dendrite outgrowth in embryonic hippocampal neurons. J Neurosci 28(41):10257–10271
Baig S, Joseph SA, Tayler H, Abraham R, Owen MJ, Williams J, Kehoe PG, Love S (2010) Distribution and expression of PICALM in Alzheimer disease. J Neuropathol Exp Neurol 69(10):1071–1077. doi:10.1097/NEN.0b013e3181f52e01
Xiao Q, Gil SC, Yan P, Wang Y, Han S, Gonzales E, Perez R, Cirrito JR, Lee JM (2012) Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem 287(25):21279–21289. doi:10.1074/jbc.M111.338376
Dreyling M, Martinez-Climent J, Zheng M, Mao J, Rowley J, Bohlander S (1996) The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family. Proc Natl Acad Sci 93(10):4804–4809
Greiner O, Bornhauser BC, Delabesse E, Ballerini P, Landman-Parker J, Bourquin JP (2007) The CALM-AF10 fusion is a rare event in acute megakaryoblastic leukemia. Leukemia 21(12):2568–2569. doi:10.1038/sj.leu.2404835
Klebig ML, Wall MD, Potter MD, Rowe EL, Carpenter DA, Rinchik EM (2003) Mutations in the clathrin-assembly gene PICALM are responsible for the hematopoietic and iron metabolism abnormalities in fit1 mice. Proc Natl Acad Sci U S A 100(14):8360–8365. doi:10.1073/pnas.1432634100
Suzuki M, Tanaka H, Tanimura A, Tanabe K, Oe N, Rai S, Kon S, Fukumoto M, Takei K, Abe T (2012) The clathrin assembly protein PICALM is required for erythroid maturation and transferrin internalization in mice. PLoS One 7(2):e31854
Marsh M, McMahon HT (1999) The structural era of endocytosis. Science 285(5425):215–220
Cirrito JR, Kang J-E, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron 58(1):42–51
Kyriazis GA, Wei Z, Vandermey M, Jo D-G, Xin O, Mattson MP, Chan SL (2008) Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner implications for Alzheimer disease pathogenesis. J Biol Chem 283(37):25492–25502
Traub LM (2009) Tickets to ride: selecting cargo for clathrin-regulated internalization. Nat Rev Mol Cell Biol 10(9):583–596. doi:10.1038/nrm2751
Wu F, Yao PJ (2009) Clathrin-mediated endocytosis and Alzheimer’s disease: an update. Ageing Res Rev 8(3):147–149. doi:10.1016/j.arr.2009.03.002
Royle SJ, Lagnado L (2010) Clathrin‐mediated endocytosis at the synaptic terminal: bridging the gap between physiology and molecules. Traffic 11(12):1489–1497
Meyerholz A, Hinrichsen L, Groos S, Esk PC, Brandes G, Ungewickell EJ (2005) Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on clathrin coat formation. Traffic 6(12):1225–1234. doi:10.1111/j.1600-0854.2005.00355.x
Nixon RA (2005) Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiol Aging 26(3):373–382. doi:10.1016/j.neurobiolaging.2004.09.018
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study(GWAS) identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093. doi:10.1038/ng.440
Lee JH, Cheng R, Barral S, Reitz C, Medrano M, Lantigua R, Jimenez-Velazquez IZ, Rogaeva E, St George-Hyslop PH, Mayeux R (2011) Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch Neurol 68(3):320–328. doi:10.1001/archneurol.2010.292
Piaceri I, Bagnoli S, Lucenteforte E, Mancuso M, Tedde A, Siciliano G, Piacentini S, Bracco L, Sorbi S, Nacmias B (2011) Implication of a genetic variant at PICALM in Alzheimer’s disease patients and centenarians. J Alzheimer’s Dis JAD 24(3):409–413. doi:10.3233/JAD-2011-101791
Lambert JC, Zelenika D, Hiltunen M, Chouraki V, Combarros O, Bullido MJ, Tognoni G, Fievet N, Boland A, Arosio B, Coto E, Del Zompo M, Mateo I, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Lathrop M, Soininen H, Amouyel P (2011) Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations. Neurobiol Aging 32(4):756. doi:10.1016/j.neurobiolaging.2010.11.022, e711–755
Ferrari R, Moreno JH, Minhajuddin AT, O’Bryant SE, Reisch JS, Barber RC, Momeni P (2012) Implication of common and disease specific variants in CLU, CR1, and PICALM. Neurobiol Aging 33(8):1846. doi:10.1016/j.neurobiolaging.2012.01.110, e1847–1818
Kamboh MI, Minster RL, Demirci FY, Ganguli M, Dekosky ST, Lopez OL, Barmada MM (2012) Association of CLU and PICALM variants with Alzheimer’s disease. Neurobiol Aging 33(3):518–521. doi:10.1016/j.neurobiolaging.2010.04.015
Rosenthal SL, Wang X, Demirci FY, Barmada MM, Ganguli M, Lopez OL, Kamboh MI (2012) Beta-amyloid toxicity modifier genes and the risk of Alzheimer’s disease. Am J Neurodegener Dis 1(2):191–198
Li HL, Shi SS, Guo QH, Ni W, Dong Y, Liu Y, Sun YM, Bei W, Lu SJ, Hong Z, Wu ZY (2011) PICALM and CR1 variants are not associated with sporadic Alzheimer’s disease in Chinese patients. J Alzheimer’s Dis JAD 25(1):111–117. doi:10.3233/JAD-2011-101917
Liu G, Zhang L, Feng R, Liao M, Jiang Y, Chen Z, Zhao B, Li K (2013) Lack of association between PICALM rs3851179 polymorphism and Alzheimer’s disease in Chinese population and APOEepsilon4-negative subgroup. Neurobiol Aging 34(4):1310. doi:10.1016/j.neurobiolaging.2012.08.015, e1319–1310
Jiang T, Yu JT, Tan MS, Wang HF, Wang YL, Zhu XC, Zhang W, Tan L (2014) Genetic variation in PICALM and Alzheimer’s disease risk in Han Chinese. Neurobiol Aging 35(4):934. doi:10.1016/j.neurobiolaging.2013.09.014, e931–933
Chen LH, Kao PY, Fan YH, Ho DT, Chan CS, Yik PY, Ha JC, Chu LW, Song YQ (2012) Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer’s disease in a southern Chinese population. Neurobiol Aging 33(1):210. doi:10.1016/j.neurobiolaging.2011.09.016, e211–217
Morgen K, Ramirez A, Frolich L, Tost H, Plichta MM, Kolsch H, Rakebrandt F, Rienhoff O, Jessen F, Peters O, Jahn H, Luckhaus C, Hull M, Gertz HJ, Schroder J, Hampel H, Teipel SJ, Pantel J, Heuser I, Wiltfang J, Ruther E, Kornhuber J, Maier W, Meyer-Lindenberg A (2014) Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc. doi:10.1016/j.jalz.2013.11.001
Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Alzheimer’s Disease Genetics C, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD (2010) Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67(12):1473–1484. doi:10.1001/archneurol.2010.201
Feinkohl I, Keller M, Robertson CM, Morling JR, Williamson RM, Nee LD, McLachlan S, Sattar N, Welsh P, Reynolds RM, Russ TC, Deary IJ, Strachan MW, Price JF, Edinburgh Type 2 Diabetes Study I (2013) Clinical and subclinical macrovascular disease as predictors of cognitive decline in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 36(9):2779–2786. doi:10.2337/dc12-2241
Liu G, Zhang S, Cai Z, Ma G, Zhang L, Jiang Y, Feng R, Liao M, Chen Z, Zhao B, Li K (2013) PICALM gene rs3851179 polymorphism contributes to Alzheimer’s disease in an Asian population. Neruomol Med 15(2):384–388. doi:10.1007/s12017-013-8225-2
Ohara T, Ninomiya T, Hirakawa Y, Ashikawa K, Monji A, Kiyohara Y, Kanba S, Kubo M (2012) Association study of susceptibility genes for late-onset Alzheimer’s disease in the Japanese population. Psychiatr Genet 22(6):290–293. doi:10.1097/YPG.0b013e3283586215
Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R, Group N-LNFS (2011) Genome-wide association of familial late-onset Alzheimer’s disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet 7(2):e1001308. doi:10.1371/journal.pgen.1001308
Hohman TJ, Koran ME, Thornton-Wells T, Alzheimer’s Neuroimaging I (2013) Epistatic genetic effects among Alzheimer’s candidate genes AD. PLoS One 8(11):e80839. doi:10.1371/journal.pone.0080839
Kohannim O, Hua X, Rajagopalan P, Hibar DP, Jahanshad N, Grill JD, Apostolova LG, Toga AW, Jack CR Jr, Weiner MW, Thompson PM, Alzheimer’s Disease Neuroimaging I (2013) Multilocus genetic profiling to empower drug trials and predict brain atrophy. NeuroImage Clin 2:827–835. doi:10.1016/j.nicl.2013.05.007
Rodriguez-Rodriguez E, Sanchez-Juan P, Vazquez-Higuera JL, Mateo I, Pozueta A, Berciano J, Cervantes S, Alcolea D, Martinez-Lage P, Clarimon J, Lleo A, Pastor P, Combarros O (2013) Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer’s disease. J Neural Transm (Vienna, Austria : 1996) 120(5):807–812. doi:10.1007/s00702-012-0920-x
Barral S, Bird T, Goate A, Farlow M, Diaz-Arrastia R, Bennett D, Graff-Radford N, Boeve B, Sweet R, Stern Y (2012) Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory. Neurology 78(19):1464–1471
Verhaaren BF, Vernooij MW, Koudstaal PJ, Uitterlinden AG, van Duijn CM, Hofman A, Breteler MM, Ikram MA (2013) Alzheimer’s disease genes and cognition in the nondemented general population. Biol Psychiatry 73(5):429–434. doi:10.1016/j.biopsych.2012.04.009
Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O’Reilly S, Chibnik LB, Shulman JM, Singleton AB, Craig DW, Van Keuren-Jensen KR, Dunckley T, Bennett DA, De Jager PL, Heward C, Hardy J, Reiman EM, Huentelman MJ (2010) Association of CR1, CLU and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet 19(16):3295–3301. doi:10.1093/hmg/ddq221
Furney SJ, Simmons A, Breen G, Pedroso I, Lunnon K, Proitsi P, Hodges A, Powell J, Wahlund LO, Kloszewska I, Mecocci P, Soininen H, Tsolaki M, Vellas B, Spenger C, Lathrop M, Shen L, Kim S, Saykin AJ, Weiner MW, Lovestone S, Alzheimer’s Disease Neuroimaging I, AddNeuroMed C (2011) Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer’s disease. Mol Psychiatry 16(11):1130–1138. doi:10.1038/mp.2010.123
Bralten J, Franke B, Arias-Vasquez A, Heister A, Brunner HG, Fernandez G, Rijpkema M (2011) CR1 genotype is associated with entorhinal cortex volume in young healthy adults. Neurobiol Aging 32(11):2106. doi:10.1016/j.neurobiolaging.2011.05.017, e2107–2111
Melville SA, Buros J, Parrado AR, Vardarajan B, Logue MW, Shen L, Risacher SL, Kim S, Jun G, DeCarli C, Lunetta KL, Baldwin CT, Saykin AJ, Farrer LA, Alzheimer’s Disease Neuroimaging I (2012) Multiple loci influencing hippocampal degeneration identified by genome scan. Ann Neurol 72(1):65–75. doi:10.1002/ana.23644
Biffi A, Anderson CD, Desikan RS, Sabuncu M, Cortellini L, Schmansky N, Salat D, Rosand J, Alzheimer’s Disease Neuroimaging Initiative (2010) Genetic variation and neuroimaging measures in Alzheimer disease. Arch Neurol 67(6):677–685. doi:10.1001/archneurol.2010.108
Jones EL, Mok K, Hanney M, Harold D, Sims R, Williams J, Ballard C (2013) Evidence that PICALM affects age at onset of Alzheimer’s dementia in Down syndrome. Neurobiol Aging 34(10):2441. doi:10.1016/j.neurobiolaging.2013.03.018, e2441–2445
Thambisetty M, An Y, Tanaka T (2013) Alzheimer’s disease risk genes and the age-at-onset phenotype. Neurobiol Aging 34(11):2696. doi:10.1016/j.neurobiolaging.2013.05.028, e2691–2695
Chibnik LB, Shulman JM, Leurgans SE, Schneider JA, Wilson RS, Tran D, Aubin C, Buchman AS, Heward CB, Myers AJ, Hardy JA, Huentelman MJ, Corneveaux JJ, Reiman EM, Evans DA, Bennett DA, De Jager PL (2011) CR1 is associated with amyloid plaque burden and age-related cognitive decline. Ann Neurol 69(3):560–569. doi:10.1002/ana.22277
Mengel-From J, Christensen K, McGue M, Christiansen L (2011) Genetic variations in the CLU and PICALM genes are associated with cognitive function in the oldest old. Neurobiol Aging 32(3):554. doi:10.1016/j.neurobiolaging.2010.07.016, e557–511
Schmidt C, Wolff M, von Ahsen N, Zerr I (2012) Alzheimer’s disease: genetic polymorphisms and rate of decline. Dement Geriatr Cogn Disord 33(2–3):84–89. doi:10.1159/000336790
Sweet RA, Seltman H, Emanuel JE, Lopez OL, Becker JT, Bis JC, Weamer EA, DeMichele-Sweet MA, Kuller LH (2012) Effect of Alzheimer’s disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study. Am J Psychiatry 169(9):954–962. doi:10.1176/appi.ajp.2012.11121815
Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S, Van Eerdewegh P, Soares H, Alzheimer’s Disease Neuroimaging I (2011) Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer’s disease. PLoS One 6(2):e16616. doi:10.1371/journal.pone.0016616
Ruiz A, Hernandez I, Ronsende-Roca M, Gonzalez-Perez A, Rodriguez-Noriega E, Ramirez-Lorca R, Mauleon A, Moreno-Rey C, Boswell L, Tune L, Valero S, Alegret M, Gayan J, Becker JT, Real LM, Tarraga L, Ballard C, Terrin M, Sherman S, Payami H, Lopez OL, Mintzer JE, Boada M (2013) Exploratory analysis of seven Alzheimer’s disease genes: disease progression. Neurobiol Aging 34(4):1310. doi:10.1016/j.neurobiolaging.2012.08.014, e1311–1317
Hu X, Pickering EH, Hall SK, Naik S, Liu YC, Soares H, Katz E, Paciga SA, Liu W, Aisen PS, Bales KR, Samad TA, John SL (2011) Genome-wide association study (GWAS) identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment (MCI). Translatl Psychiatry 1:e54. doi:10.1038/tp.2011.50
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093
Jun G, Naj AC, Beecham GW, Wang L-S, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R (2010) Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67(12):1473–1484
Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43(5):436–441
Schnetz-Boutaud NC, Hoffman J, Coe JE, Murdock DG, Pericak-Vance MA, Haines JL (2012) Identification and confirmation of an exonic splicing enhancer variation in exon 5 of the Alzheimer disease associated PICALM gene. Ann Hum Genet 76(6):448–453. doi:10.1111/j.1469-1809.2012.00727.x
Kok EH, Luoto T, Haikonen S, Goebeler S, Haapasalo H, Karhunen PJ (2011) CLU, CR1 and PICALM genes associate with Alzheimer’s-related senile plaques. Alzheimers Res Ther 3(2):12. doi:10.1186/alzrt71
Roses AD (1994) Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on APOE genotype and duration of disease. J Neuropathol Exp Neurol 53(5):429–437
Yotter RA, Doshi J, Clark V, Sojkova J, Zhou Y, Wong DF, Ferrucci L, Resnick SM, Davatzikos C (2013) Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden. Neurobiol Aging 34(12):2835–2842. doi:10.1016/j.neurobiolaging.2013.05.030
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(9634):216–223. doi:10.1016/S0140-6736(08)61075-2
Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T (2010) A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30(14):4845–4856
Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766
Vetrivel KS, Thinakaran G (2006) Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology 66(2 Suppl 1):S69–S73. doi:10.1212/01.wnl.0000192107.17175.39
Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58(1):42–51. doi:10.1016/j.neuron.2008.02.003
Rudinskiy N, Grishchuk Y, Vaslin A, Puyal J, Delacourte A, Hirling H, Clarke PG, Luthi-Carter R (2009) Calpain hydrolysis of alpha- and beta2-adaptins decreases clathrin-dependent endocytosis and may promote neurodegeneration. J Biol Chem 284(18):12447–12458. doi:10.1074/jbc.M804740200
Kim JA, Kim HL (2001) Cleavage of purified neuronal clathrin assembly protein (CALM) by caspase 3 and calpain. Exp Mol Med 33(4):245–250. doi:10.1038/emm.2001.40
Treusch S, Hamamichi S, Goodman JL, Matlack KE, Chung CY, Baru V, Shulman JM, Parrado A, Bevis BJ, Valastyan JS, Han H, Lindhagen-Persson M, Reiman EM, Evans DA, Bennett DA, Olofsson A, DeJager PL, Tanzi RE, Caldwell KA, Caldwell GA, Lindquist S (2011) Functional links between Abeta toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science (New York, NY) 334(6060):1241–1245. doi:10.1126/science.1213210
D’Angelo F, Vignaud H, Di Martino J, Salin B, Devin A, Cullin C, Marchal C (2013) A yeast model for amyloid-beta aggregation exemplifies the role of membrane trafficking and PICALM in cytotoxicity. Dis Models Mech 6(1):206–216. doi:10.1242/dmm.010108
Ando K, Brion JP, Stygelbout V, Suain V, Authelet M, Dedecker R, Chanut A, Lacor P, Lavaur J, Sazdovitch V, Rogaeva E, Potier MC, Duyckaerts C (2013) Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains. Acta Neuropathol 125(6):861–878. doi:10.1007/s00401-013-1111-z
Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L (2014) Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy. Neurobiol Aging 35(5):941–957. doi:10.1016/j.neurobiolaging.2013.11.019
Vingtdeux V, Chandakkar P, Zhao H, d’Abramo C, Davies P, Marambaud P (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J Off Publ Fed Am Soc Exp Biol 25(1):219–231. doi:10.1096/fj.10-167361
Tian Y, Bustos V, Flajolet M, Greengard P (2011) A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway. FASEB J Off Publ Fed Am Soc Exp Biol 25(6):1934–1942. doi:10.1096/fj.10-175158
Tian Y, Chang JC, Fan EY, Flajolet M, Greengard P (2013) Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer’s APP-CTF for terminal degradation via autophagy. Proc Natl Acad Sci U S A 110(42):17071–17076. doi:10.1073/pnas.1315110110
Tian Y, Chang JC, Greengard P, Flajolet M (2014) The convergence of endosomal and autophagosomal pathways: implications for APP-CTF degradation. Autophagy 10(4):694–696
Schjeide BM, Schnack C, Lambert JC, Lill CM, Kirchheiner J, Tumani H, Otto M, Tanzi RE, Lehrach H, Amouyel P, von Arnim CA, Bertram L (2011) The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. Arch Gen Psychiatry 68(2):207–213. doi:10.1001/archgenpsychiatry.2010.196
Kauwe JS, Cruchaga C, Karch CM, Sadler B, Lee M, Mayo K, Latu W, Su’a M, Fagan AM, Holtzman DM, Morris JC, Alzheimer’s Disease Neuroimaging I, Goate AM (2011) Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid(CSF) biomarkers for Alzheimer’s disease. PLoS One 6(2):e15918. doi:10.1371/journal.pone.0015918
Dean RA, Shaw LM (2010) Use of cerebrospinal fluid biomarkers for diagnosis of incipient Alzheimer disease in patients with mild cognitive impairment. Clin Chem 56(1):7–9. doi:10.1373/clinchem.2009.134692
Schott JM, Investigators A (2012) Using CSF biomarkers to replicate genetic associations in Alzheimer’s disease. Neurobiol Aging 33(7):1486. doi:10.1016/j.neurobiolaging.2011.02.008, e1489–1415
Katz B (2003) Neural transmitter release: from quantal secretion to exocytosis and beyond. J Neurocytol 32(5–8):437–446. doi:10.1023/B:NEUR.0000020603.84188.03
Jahn R, Scheller RH (2006) SNAREs—engines for membrane fusion. Nat Rev Mol Cell Biol 7(9):631–643. doi:10.1038/nrm2002
Schweizer FE, Ryan TA (2006) The synaptic vesicle: cycle of exocytosis and endocytosis. Curr Opin Neurobiol 16(3):298–304. doi:10.1016/j.conb.2006.05.006
Harel A, Wu F, Mattson MP, Morris CM, Yao PJ (2008) Evidence for CALM in directing VAMP2 trafficking. Traffic 9(3):417–429. doi:10.1111/j.1600-0854.2007.00694.x
Miller SE, Sahlender DA, Graham SC, Honing S, Robinson MS, Peden AA, Owen DJ (2011) The molecular basis for the endocytosis of small R-SNAREs by the clathrin adaptor CALM. Cell 147(5):1118–1131. doi:10.1016/j.cell.2011.10.038
Russell CL, Semerdjieva S, Empson RM, Austen BM, Beesley PW, Alifragis P (2012) Amyloid-beta acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2. PLoS One 7(8):e43201. doi:10.1371/journal.pone.0043201
Harel A, Mattson MP, Yao PJ (2011) CALM, a clathrin assembly protein, influences cell surface GluR2 abundance. Neruomol Med 13(1):88–90. doi:10.1007/s12017-010-8142-6
Tokuoka H, Goda Y (2008) Activity-dependent coordination of presynaptic release probability and postsynaptic GluR2 abundance at single synapses. Proc Natl Acad Sci U S A 105(38):14656–14661. doi:10.1073/pnas.0805705105
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282(15):11590–11601. doi:10.1074/jbc.M607483200
Bradley MA, Xiong-Fister S, Markesbery WR, Lovell MA (2012) Elevated 4-hydroxyhexenal in Alzheimer’s disease (AD) progression. Neurobiol Aging 33(6):1034–1044. doi:10.1016/j.neurobiolaging.2010.08.016
Mangialasche F, Xu W, Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, Cecchetti R, Baglioni M, Simmons A, Soininen H, Tsolaki M, Kloszewska I, Vellas B, Lovestone S, Mecocci P, AddNeuroMed C (2012) Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging 33(10):2282–2290. doi:10.1016/j.neurobiolaging.2011.11.019
Whiley L, Sen A, Heaton J, Proitsi P, Garcia-Gomez D, Leung R, Smith N, Thambisetty M, Kloszewska I, Mecocci P, Soininen H, Tsolaki M, Vellas B, Lovestone S, Legido-Quigley C, AddNeuroMed C (2014) Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease. Neurobiol Aging 35(2):271–278. doi:10.1016/j.neurobiolaging.2013.08.001
Shi H, Belbin O, Medway C, Brown K, Kalsheker N, Carrasquillo M, Proitsi P, Powell J, Lovestone S, Goate A, Younkin S, Passmore P, Genetic and Environmental Risk for Alzheimer’s Disease Consortium, Morgan K, Alzheimer’s Research UK Consortium (2012) Genetic variants influencing human aging from late-onset Alzheimer’s disease (LOAD) genome-wide association studies (GWAS). Neurobiol Aging 33(8):1849. doi:10.1016/j.neurobiolaging.2012.02.014, e1845–1818
Chen JM, Chang CW, Chang TH, Hsu CC, Horng JT, Sheu WH (2014) Effects of statins on incident dementia in patients with type 2 DM: a population-based retrospective cohort study in Taiwan. PLoS One 9(2):e88434. doi:10.1371/journal.pone.0088434
Metais C, Brennan K, Mably AJ, Scott M, Walsh DM, Herron CE (2014) Simvastatin treatment preserves synaptic plasticity in AbetaPPswe/PS1dE9 mice. J Alzheimer’s Dis JAD 39(2):315–329. doi:10.3233/JAD-130257
Wong WB, Lin VW, Boudreau D, Devine EB (2013) Statins in the prevention of dementia and Alzheimer’s disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf 22(4):345–358. doi:10.1002/pds.3381
Papadopoulos P, Tong XK, Hamel E (2014) Selective benefits of simvastatin in bitransgenic APPSwe, Ind/TGF-beta1 mice. Neurobiol Aging 35(1):203–212. doi:10.1016/j.neurobiolaging.2013.07.010
Olgiati P, Politis AM, Papadimitriou GN, De Ronchi D, Serretti A (2011) Genetics of late-onset Alzheimer’s disease: update from the alzgene database and analysis of shared pathways. Int J Alzheimers Dis 2011:832379. doi:10.4061/2011/832379
Morgan K (2011) The three new pathways leading to Alzheimer’s disease. Neuropathol Appl Neurobiol 37(4):353–357. doi:10.1111/j.1365-2990.2011.01181.x
Eisenstein M (2011) Genetics: finding risk factors. Nature 475(7355):S20–S22. doi:10.1038/475S20a
De Chiara G, Marcocci ME, Sgarbanti R, Civitelli L, Ripoli C, Piacentini R, Garaci E, Grassi C, Palamara AT (2012) Infectious agents and neurodegeneration. Mol Neurobiol 46(3):614–638. doi:10.1007/s12035-012-8320-7
Ball MJ, Lukiw WJ, Kammerman EM, Hill JM (2013) Intracerebral propagation of Alzheimer’s disease: strengthening evidence of a herpes simplex virus etiology. Alzheimer’s Dement J Alzheimer’s Assoc 9(2):169–175. doi:10.1016/j.jalz.2012.07.005
Wozniak MA, Itzhaki RF (2013) Intravenous immunoglobulin reduces beta amyloid and abnormal tau formation caused by herpes simplex virus type 1. J Neuroimmunol 257(1–2):7–12. doi:10.1016/j.jneuroim.2013.01.005
Agostini S, Clerici M, Mancuso R (2014) How plausible is a link between HSV-1 infection and Alzheimer’s disease? Expert Rev Anti-Infect Ther 12(3):275–278. doi:10.1586/14787210.2014.887442
Mancuso R, Baglio F, Cabinio M, Calabrese E, Hernis A, Nemni R, Clerici M (2014) Titers of herpes simplex virus type 1 antibodies positively correlate with grey matter volumes in Alzheimer’s disease. J Alzheimer’s Dis 38(4):741–745. doi:10.3233/JAD-130977
Piacentini R, Civitelli L, Ripoli C, Marcocci ME, De Chiara G, Garaci E, Azzena GB, Palamara AT, Grassi C (2011) HSV-1 promotes Ca2+-mediated APP phosphorylation and Abeta accumulation in rat cortical neurons. Neurobiol Aging 32(12):2323. doi:10.1016/j.neurobiolaging.2010.06.009, e2313–2326
Licastro F, Carbone I, Ianni M, Porcellini E (2011) Gene signature in Alzheimer’s disease and environmental factors: the virus chronicle. J Alzheimer’s Dis 27(4):809–817. doi:10.3233/JAD-2011-110755
Carter C (2011) Alzheimer’s disease: APP, gamma secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and their relationships with Herpes simplex, C. pneumoniae, other suspect pathogens, and the immune system. Int J Alzheimers Dis 2011:501862. doi:10.4061/2011/501862
Carter CJ (2010) APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle. Neurosci Lett 483(2):96–100. doi:10.1016/j.neulet.2010.07.066
Carter CJ (2010) Alzheimer’s disease: a pathogenetic autoimmune disorder caused by herpes simplex in a gene-dependent manner. Int J Alzheimers Dis 2010:140539. doi:10.4061/2010/140539
Crespo AC, Silva B, Marques L, Marcelino E, Maruta C, Costa S, Timoteo A, Vilares A, Couto FS, Faustino P, Correia AP, Verdelho A, Porto G, Guerreiro M, Herrero A, Costa C, de Mendonca A, Costa L, Martins M (2014) Genetic and biochemical markers in patients with Alzheimer’s disease support a concerted systemic iron homeostasis dysregulation. Neurobiol Aging 35(4):777–785. doi:10.1016/j.neurobiolaging.2013.10.078
Huang XT, Qian ZM, He X, Gong Q, Wu KC, Jiang LR, Lu LN, Zhu ZJ, Zhang HY, Yung WH, Ke Y (2014) Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer’s disease. Neurobiol Aging 35(5):1045–1054. doi:10.1016/j.neurobiolaging.2013.11.004
Wu WS, Zhao YS, Shi ZH, Chang SY, Nie GJ, Duan XL, Zhao SM, Wu Q, Yang ZL, Zhao BL, Chang YZ (2013) Mitochondrial ferritin attenuates beta-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways. Antioxid Redox Signal 18(2):158–169. doi:10.1089/ars.2011.4285
Yang H, Yang M, Guan H, Liu Z, Zhao S, Takeuchi S, Yanagisawa D, Tooyama I (2013) Mitochondrial ferritin in neurodegenerative diseases. Neurosci Res 77(1–2):1–7. doi:10.1016/j.neures.2013.07.005
Faux NG, Rembach A, Wiley J, Ellis KA, Ames D, Fowler CJ, Martins RN, Pertile KK, Rumble RL, Trounson B, Masters CL, The ARG, Bush AI (2014) An anemia of Alzheimer’s disease. Mol Psychiatry. doi:10.1038/mp.2013.178
Grant WB (2014) Trends in diet and Alzheimer’s disease during the nutrition transition in Japan and developing countries. J Alzheimer’s Dis 38(3):611–620. doi:10.3233/JAD-130719
Scotland PB, Heath JL, Conway AE, Porter NB, Armstrong MB, Walker JA, Klebig ML, Lavau CP, Wechsler DS (2012) The PICALM protein plays a key role in iron homeostasis and cell proliferation. PLoS One 7(8):e44252. doi:10.1371/journal.pone.0044252
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (81000544, 81171209, and 81371406) and Shandong Provincial Natural Science Foundation, China (ZR2010HQ004 and ZR2011HZ001).
Conflict of Interest
The authors declare no conflicts of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Xu, W., Tan, L. & Yu, JT. The Role of PICALM in Alzheimer’s Disease. Mol Neurobiol 52, 399–413 (2015). https://doi.org/10.1007/s12035-014-8878-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-014-8878-3