CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 N141I neurons

Arendt T, Bigl V, Arendt A, Tennstedt A (1983) Loss of neurons in the nucleus basalis of Meynert in Alzheimer’s disease, paralysis agitans and Korsakoff’s disease. Acta Neuropathol 61:101–108

Armijo E, Gonzalez C, Shahnawaz M, Flores A, Davis B, Soto C (2017) Increased susceptibility to Aβ toxicity in neuronal cultures derived from familial Alzheimer’s disease (PSEN1 A246E) induced pluripotent stem cells. Neurosci Lett 639:74–81. doi: 10.1016/j.neulet.2016.12.060

Bardy C, van den Hurk M, Eames T, Marchand C, Hernandez RV, Kellogg M, Gorris M, Galet B, Palomares V, Brown J, Bang AG, Mertens J, Böhnke L, Boyer L, Simon S, Gage FH (2015) Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc Natl Acad Sci U S A 112:E2725–E2734. doi: 10.1073/pnas.1504393112

Bissonnette CJ, Lyass L, Bhattacharyya BJ, Belmadani A, Miller RJ, Kessler JA (2011) The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells 29:802–811. doi: 10.1002/stem.626

Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945. doi: 10.1016/S0896-6273(00)80974-5

Bowen DM, Smith CB, White P, Davison AN (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99:459–496

Bragina O, Sergejeva S, Serg M, Žarkovsky T, Maloverjan A, Kogerman P, Žarkovsky A (2010) Smoothened agonist augments proliferation and survival of neural cells. Neurosci Lett 482:81–85. doi: 10.1016/j.neulet.2010.06.068

Briggs CA, Schneider C, Richardson JC, Stutzmann GE (2013) Beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer’s disease mice. Neurobiol Aging 34:1632–1643. doi: 10.1016/j.neurobiolaging.2012.12.013

Brown JT, Chin J, Leiser SC, Pangalos MN, Randall AD (2011) Altered intrinsic neuronal excitability and reduced Na+ currents in a mouse model of Alzheimer’s disease. Neurobiol Aging 32:2109.e1-2109.e14. doi: 10.1016/j.neurobiolaging.2011.05.025

Brueggen K, Dyrba M, Barkhof F, Hausner L, Filippi M, Nestor PJ, Hauenstein K, Klöppel S, Grothe MJ, Kasper E, Teipel SJ (2015) Basal forebrain and hippocampus as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment – a multicenter DTI and Volumetry study. J Alzheimers Dis 48:197–204. doi: 10.3233/JAD-150063

Bruey JM, Bruey-Sedano N, Newman R, Chandler S, Stehlik C, Reed JC (2004) PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. J Biol Chem 279:51897–51907. doi: 10.1074/jbc.M406741200

Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27:275–280. doi: 10.1038/nbt.1529

Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, Kühn R (2015) Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol 33:543–548. doi: 10.1038/nbt.3198

Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, de Bernard M (2013) Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One 8:e55375. doi: 10.1371/journal.pone.0055375

Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823. doi: 10.1126/science.1231143

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

Crompton LA, Byrne ML, Taylor H, Kerrigan TL, Bru-Mercier G, Badger JL, Barbuti PA, Jo J, Tyler SJ, Allen SJ, Kunath T, Cho K, Caldwell MA (2013) Stepwise, non-adherent differentiation of human pluripotent stem cells to generate basal forebrain cholinergic neurons via hedgehog signaling. Stem Cell Res 11:1206–1221. doi: 10.1016/j.scr.2013.08.002

Cummings DM, Liu W, Portelius E, Bayram S, Yasvoina M, Ho S-H, Smits H, Ali SS, Steinberg R, Pegasiou C-M, James OT, Matarin M, Richardson JC, Zetterberg H, Blennow K, Hardy JA, Salih DA, Edwards FA (2015) First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression. Brain 138:1992–2004. doi: 10.1093/brain/awv127

Danjo T, Eiraku M, Muguruma K, Watanabe K, Kawada M, Yanagawa Y, Rubenstein JLR, Sasai Y (2011) Subregional specification of embryonic stem cell-derived ventral Telencephalic tissues by timed and combinatory treatment with extrinsic signals. J Neurosci 31:1919–1933. doi: 10.1523/JNEUROSCI.5128-10.2011

Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet (London, England). 2:1403

Davis KL, Mohs RC, Davis BM, Horvath TB, Greenwald BS, Rosen WG, Levy MI, Johns CA (1983) Oral physostigmine in Alzheimer’s disease. Psychopharmacol Bull 19:451–453

De Strooper B After Solanezumab: Where Should Alzheimer’s Research Go? | ALZFORUM. 2017

Echeverria V, Berman DE, Arancio O (2007) Oligomers of beta-amyloid peptide inhibit BDNF-induced arc expression in cultured cortical neurons. Curr Alzheimer Res 4:518–521

Epelbaum S, Genthon R, Cavedo E, Habert MO, Lamari F, Gagliardi G, Lista S, Teichmann M, Bakardjian H, Hampel H, Dubois B (2017) Preclinical Alzheimer’s disease: a systematic review of the cohorts underlying the concept. Alzheimers Dement. doi: 10.1016/j.jalz.2016.12.003

Etcheberrigaray R, Ito E, Kim CS, Alkon DL (1994) Soluble beta-amyloid induction of Alzheimer’s phenotype for human fibroblast K+ channels. Science 264:276–279

Flandin P, Zhao Y, Vogt D, Jeong J, Long J, Potter G, Westphal H, Rubenstein JLR (2011) Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron 70:939–950. doi: 10.1016/j.neuron.2011.04.020

Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147. doi: 10.1136/JNNP.66.2.137

Gamzu ER, Thal LJ, Davis KL (1990) Therapeutic trials using tacrine and other cholinesterase inhibitors. Adv Neurol 51:241–245

Gandy S, Doeven MK, Poolman B (2006) Alzheimer disease: presenilin springs a leak. Nat Med 12:1121–1123. doi: 10.1038/nm1006-1121

Goulburn AL, Alden D, Davis RP, Micallef SJ, Ng ES, Yu QC, Lim SM, Soh C-L, Elliott DA, Hatzistavrou T, Bourke J, Watmuff B, Lang RJ, Haynes JM, Pouton CW, Giudice A, Trounson AO, Anderson SA, Stanley EG, Elefanty AG (2011a) A targeted NKX2.1 human embryonic stem cell reporter line enables identification of human basal forebrain derivatives. Stem Cells 29:462–473. doi: 10.1002/stem.587

Guo Q, Fu W, Holtsberg FW, Steiner SM, Mattson MP (1999) Superoxide mediates the cell-death-enhancing action of presenilin-1 mutations. J Neurosci Res 56:457–470. doi: 10.1002/(SICI)1097-4547(19990601)56:5<457::AID-JNR2>3.0.CO;2-P

Gustot A, Gallea JI, Sarroukh R, Celej MS, Ruysschaert J-M, Raussens V (2015) Amyloid fibrils are the molecular trigger of inflammation in Parkinson’s disease. Biochem J 471:323–333. doi: 10.1042/BJ20150617

Hager K, Baseman AS, Nye JS, Brashear HR, Han J, Sano M, Davis B, Richards HM (2014) Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease. Neuropsychiatr Dis Treat 10:391–401. doi: 10.2147/NDT.S57909

Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9:857–865. doi: 10.1038/ni.1636

Heine VM, Griveau A, Chapin C, Ballard PL, Chen JK, Rowitch DH (2011) A small-molecule smoothened agonist prevents Glucocorticoid-induced neonatal Cerebellar injury. Sci Transl Med 3:105ra104. doi: 10.1126/scitranslmed.3002731

Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548. doi: 10.0000/PMID2341813

Hoxha E, Boda E, Montarolo F, Parolisi R, Tempia F (2012) Excitability and synaptic alterations in the cerebellum of APP/PS1 mice. PLoS One 7:e34726. doi: 10.1371/journal.pone.0034726

Hu Y, Qu Z, Cao S, Li Q, Ma L, Krencik R, Xu M, Liu Y (2016) Directed differentiation of basal forebrain cholinergic neurons from human pluripotent stem cells. J Neurosci Methods 266:42–49. doi: 10.1016/j.jneumeth.2016.03.017

Hunsberger JG, Rao M, Kurtzberg J, Bulte JWM, Atala A, LaFerla FM, Greely HT, Sawa A, Gandy S, Schneider LS, Doraiswamy PM (2016) Accelerating stem cell trials for Alzheimer’s disease. Lancet Neurol 15:219–230. doi: 10.1016/S1474-4422(15)00332-4

Jack CR, Wiste HJ, Weigand SD, Knopman DS, Lowe V, Vemuri P, Mielke MM, Jones DT, Senjem ML, Gunter JL, Gregg BE, Pankratz VS, Petersen RC (2013) Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity. Neurology 81:1732–1740. doi: 10.1212/01.wnl.0000435556.21319.e4

Kinoshita T, Wang Y, Hasegawa M, Imamura R, Suda T (2005) PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion. J Biol Chem 280:21720–21725. doi: 10.1074/jbc.M410057200

Kruglikov I, Rudy B (2008) Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators. Neuron 58:911–924. doi: 10.1016/j.neuron.2008.04.024

Levy-Lahad E, Wasco W, Poorkaj P, Romano D, Oshima J, Pettingell W, Yu C, Jondro P, Schmidt S, Wang K et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977. doi: 10.1126/science.7638622

Liu D, Pitta M, Lee J-H, Ray B, Lahiri DK, Furukawa K, Mughal M, Jiang H, Villarreal J, Cutler RG, Greig NH, Mattson MP (2010) The KATP channel activator diazoxide ameliorates amyloid-β and tau pathologies and improves memory in the 3xTgAD mouse model of Alzheimer’s disease. J Alzheimers Dis 22:443–457. doi: 10.3233/JAD-2010-101017

Liu L, Chan C (2014) The role of inflammasome in Alzheimer’s disease. Ageing Res Rev 15:6–15. doi: 10.1016/j.arr.2013.12.007

Liu Y, Weick JP, Liu H, Krencik R, Zhang X, Ma L, Zhou G, Ayala M, Zhang S-C (2013) Medial ganglionic eminence–like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol 31:440–447. doi: 10.1038/nbt.2565

Mahairaki V, Ryu J, Peters A, Chang Q, Li T, Park TS, Burridge PW, Talbot CC, Asnaghi L, Martin LJ, Zambidis ET, Koliatsos VE, Koliatsos VE (2014) Induced pluripotent stem cells from familial Alzheimer’s disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev 23:2996–3010. doi: 10.1089/scd.2013.0511

Marcantoni A, Raymond EF, Carbone E, Marie H (2014) Firing properties of entorhinal cortex neurons and early alterations in an Alzheimer’s disease transgenic model. Pflugers Arch 466:1437–1450. doi: 10.1007/s00424-013-1368-z

Marchani EE, Bird TD, Steinbart EJ, Rosenthal E, Yu C-E, Schellenberg GD, Wijsman EM (2010) Evidence for three loci modifying age-at-onset of Alzheimer’s disease in early-onset PSEN2 families. Am J Med Genet B Neuropsychiatr Genet 153B:1031–1041. doi: 10.1002/ajmg.b.31072

Maroof AM, Keros S, Tyson JA, Ying S-W, Ganat YM, Merkle FT, Liu B, Goulburn A, Stanley EG, Elefanty AG, Widmer HR, Eggan K, Goldstein PA, Anderson SA, Studer L (2013) Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12:559–572. doi: 10.1016/j.stem.2013.04.008

Minkiewicz J, de Rivero Vaccari JP, Keane RW (2013) Human astrocytes express a novel NLRP2 inflammasome. Glia 61:1113–1121. doi: 10.1002/glia.22499

Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338. doi: 10.1101/cshperspect.a006338

Müller U, Winter P, Graeber MB (2011) Alois Alzheimer’s case, Auguste D., did not carry the N141I mutation in &lt;emph type=&quot;ital&quot;&gt;PSEN2&lt;/emph&gt; characteristic of Alzheimer disease in Volga Germans. Arch Neurol 68:1210. doi: 10.1001/archneurol.2011.218

Nava-Mesa MO, Jiménez-Díaz L, Yajeya J, Navarro-Lopez JD (2013) Amyloid-β induces synaptic dysfunction through G protein-gated inwardly rectifying potassium channels in the fimbria-CA3 hippocampal synapse. Front Cell Neurosci 7:117. doi: 10.3389/fncel.2013.00117

Nelson O, Supnet C, Tolia A, Horre K, De Strooper B, Bezprozvanny I (2011) Mutagenesis mapping of the Presenilin 1 calcium leak conductance pore. J Biol Chem 286:22339–22347. doi: 10.1074/jbc.M111.243063

Nieweg K, Andreyeva A, van Stegen B, Tanriöver G, Gottmann K (2015) Alzheimer’s disease-related amyloid-β induces synaptotoxicity in human iPS cell-derived neurons. Cell Death Dis 6:e1709. doi: 10.1038/cddis.2015.72

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

Onos KD, Sukoff Rizzo SJ, Howell GR, Sasner M (2016) Toward more predictive genetic mouse models of Alzheimer’s disease. Brain Res Bull 122:1–11. doi: 10.1016/j.brainresbull.2015.12.003

Oyama F, Sawamura N, Kobayashi K, Morishima-Kawashima M, Kuramochi T, Ito M, Tomita T, Maruyama K, Saido TC, Iwatsubo T, Capell A, Walter J, Grünberg J, Ueyama Y, Haass C, Ihara Y (1998) Mutant presenilin 2 transgenic mouse: effect on an age-dependent increase of amyloid beta-protein 42 in the brain. J Neurochem 71:313–322

Paull D, Sevilla A, Zhou H, Hahn AK, Kim H, Napolitano C, Tsankov A, Shang L, Krumholz K, Jagadeesan P, Woodard CM, Sun B, Vilboux T, Zimmer M, Forero E, Moroziewicz DN, Martinez H, Malicdan MCV, Weiss KA, Vensand LB, Dusenberry CR, Polus H, Sy KTL, Kahler DJ, Gahl WA, Solomon SL, Chang S, Meissner A, Eggan K, Noggle SA (2015) Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells. Nat Methods 12:885–892. doi: 10.1038/nmeth.3507

Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE (1977) Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 34:247–265

Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, Galluzzi S, Marizzoni M, Frisoni GB (2016) Brain atrophy in Alzheimer’s disease and aging. Ageing Res Rev 30:25–48. doi: 10.1016/j.arr.2016.01.002

Price DL, Tanzi RE, Borchelt DR, Sisodia SS (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32:461–493. doi: 10.1146/annurev.genet.32.1.461

Proulx É, Fraser P, McLaurin J, Lambe EK (2015) Impaired cholinergic excitation of prefrontal attention circuitry in the TgCRND8 model of Alzheimer’s disease. J Neurosci 35:12779–12791. doi: 10.1523/JNEUROSCI.4501-14.2015

Pruszak J, Sonntag KC, Aung MH, Sanchez-Pernaute R, Isacson O (2007) Markers and methods for cell sorting of human embryonic stem cell-derived neural cell populations. Stem Cells 25(9):2257–2268 Epub 2007 Jun 21. PubMed PMID: 17588935 ; PubMed Central PMCID: PMC2238728

Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308. doi: 10.1038/nprot.2013.143

Ren S-C, Shao H, Ji W-G, Jiang H-H, Xu F, Chen P-Z, Mi Z, Wen B, Zhu G-X, Zhu Z-R (2015) Riluzole prevents soluble a β 1–42 oligomers-induced perturbation of spontaneous discharge in the hippocampal CA1 region of rats. Amyloid 22:36–44. doi: 10.3109/13506129.2014.990558

Richardson CD, Ray GJ, DeWitt MA, Curie GL, Corn JE (2016) Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol 34:339–344. doi: 10.1038/nbt.3481

Ripoli C, Cocco S, Li Puma DD, Piacentini R, Mastrodonato A, Scala F, Puzzo D, D’Ascenzo M, Grassi C (2014) Intracellular accumulation of Amyloid- (a ) protein plays a major role in a -induced alterations of Glutamatergic synaptic transmission and plasticity. J Neurosci 34:12893–12903. doi: 10.1523/JNEUROSCI.1201-14.2014

Roder S, Danober L, Pozza M, Lingenhoehl K, Wiederhold K-H, Olpe H-R (2003) Electrophysiological studies on the hippocampus and prefrontal cortex assessing the effects of amyloidosis in amyloid precursor protein 23 transgenic mice. Neuroscience 120:705–720. doi: 10.1016/S0306-4522(03)00381-6

Rylett RJ, Ball MJ, Colhoun EH (1983) Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer’s disease. Brain Res 289:169–175

Sachse CC, Kim YH, Agsten M, Huth T, Alzheimer C, Kovacs DM, Kim DY (2013) BACE1 and presenilin/ -secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels. FASEB J 27:2458–2467. doi: 10.1096/fj.12-214056

Sawamura N, Morishima-Kawashima M, Waki H, Kobayashi K, Kuramochi T, Frosch MP, Ding K, Ito M, Kim TW, Tanzi RE, Oyama F, Tabira T, Ando S, Ihara Y (2000) Mutant-presenilin 2-transgenic mice: a large increase in the levels of a beta 42 is presumably associated with the low-density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin. J Biol Chem 275:27901–27908. doi: 10.1074/jbc.M004308200

Sepulveda-Falla D, Barrera-Ocampo A, Hagel C, Korwitz A, Vinueza-Veloz MF, Zhou K, Schonewille M, Zhou H, Velazquez-Perez L, Rodriguez-Labrada R, Villegas A, Ferrer I, Lopera F, Langer T, De Zeeuw CI, Glatzel M (2014) Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis. J Clin Invest 124:1552–1567. doi: 10.1172/JCI66407

Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T, Pitsch J, Schoch S, Becker A, von der Kammer H, Remy S (2014) Dendritic structural degeneration is functionally linked to cellular Hyperexcitability in a mouse model of Alzheimer’s disease. Neuron 84:1023–1033. doi: 10.1016/j.neuron.2014.10.024

Smilansky A, Dangoor L, Nakdimon I, Ben-Hail D, Mizrachi D, Shoshan-Barmatz V (2015) The voltage-dependent Anion Channel 1 mediates Amyloid β toxicity and represents a potential target for Alzheimer disease therapy. J Biol Chem 290:30670–30683. doi: 10.1074/jbc.M115.691493

Sproul AA, Jacob S, Pre D, Kim SH, Nestor MW, Navarro-Sobrino M, Santa-Maria I, Zimmer M, Aubry S, Steele JW, Kahler DJ, Dranovsky A, Arancio O, Crary JF, Gandy S, Noggle SA (2014) Characterization and molecular profiling of PSEN1 familial Alzheimer’s disease iPSC-derived neural progenitors. PLoS One 9:e84547. doi: 10.1371/journal.pone.0084547

Stine WB, Dahlgren KN, Krafft GA, LaDu MJ (2003) In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem 278:11612–11622. doi: 10.1074/jbc.M210207200

Stutzmann GE, Caccamo A, LaFerla FM, Parker I (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in Presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24:508–513. doi: 10.1523/JNEUROSCI.4386-03.2004

Supnet C, Bezprozvanny I (2011) Presenilins function in ER calcium leak and Alzheimer’s disease pathogenesis. Cell Calcium 50:303–309. doi: 10.1016/j.ceca.2011.05.013

Takahashi K, Yamanaka S (2006) Induction of Pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. doi: 10.1016/j.cell.2006.07.024

Thal LJ, Fuld PA, Masur DM, Sharpless NS (1983) Oral physostigmine and lecithin improve memory in Alzheimer disease. Ann Neurol 13:491–496. doi: 10.1002/ana.410130504

Tomita T, Maruyama K, Saido TC, Kume H, Shinozaki K, Tokuhiro S, Capell A, Walter J, Grünberg J, Haass C, Iwatsubo T, Obata K (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc Natl Acad Sci U S A 94:2025–2030

Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee S-F, Hao Y-H, Serneels L, De Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126:981–993. doi: 10.1016/j.cell.2006.06.059

Tucker ES, Segall S, Gopalakrishna D, Wu Y, Vernon M, Polleux F, Lamantia A-S (2008) Molecular specification and patterning of progenitor cells in the lateral and medial ganglionic eminences. J Neurosci 28:9504–9518. doi: 10.1523/JNEUROSCI.2341-08.2008

Varga E, Juhász G, Bozsó Z, Penke B, Fülöp L, Szegedi V (2014) Abeta(1-42) enhances neuronal excitability in the CA1 via NR2B subunit-containing NMDA receptors. Neural Plast 2014:1–12. doi: 10.1155/2014/584314

Verdile G, Gandy SE, Martins RN (2007) The role of presenilin and its interacting proteins in the biogenesis of Alzheimer’s beta amyloid. Neurochem Res 32:609–623. doi: 10.1007/s11064-006-9131-x

Wang X, Zhang X-G, Zhou T-T, Li N, Jang C-Y, Xiao Z-C, Ma Q-H, Li S (2016) Elevated neuronal excitability due to modulation of the voltage-gated Sodium Channel Nav1.6 by Aβ1−42. Front Neurosci 10:94. doi: 10.3389/fnins.2016.00094

Wicklund L, Leão RN, Strömberg A-M, Mousavi M, Hovatta O, Nordberg A, Marutle A (2010) Β-amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic neurons. PLoS One 5:e15600. doi: 10.1371/journal.pone.0015600

Wolfe MS, Selkoe DJ, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and |[gamma]|-secretase activity. Nature 398:513–517. doi: 10.1038/19077

Xu H, Sakiyama-Elbert SE (2015) Directed differentiation of V3 Interneurons from mouse embryonic stem cells. Stem Cells Dev 24:2723–2732. doi: 10.1089/scd.2015.0122

Xu W, Fitzgerald S, Nixon RA, Levy E, Wilson DA (2015) Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer’s disease. Exp Neurol 264:82–91. doi: 10.1016/j.expneurol.2014.12.008

Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20:4530–4539. doi: 10.1093/hmg/ddr394

Yue W, Li Y, Zhang T, Jiang M, Qian Y, Zhang M, Sheng N, Feng S, Tang K, Yu X, Shu Y, Yue C, Jing N (2015) ESC-derived basal forebrain cholinergic neurons ameliorate the cognitive symptoms associated with Alzheimer’s disease in mouse models. Stem Cell Rep 5:776–790. doi: 10.1016/j.stemcr.2015.09.010