Three Dimensional Human Neuro-Spheroid Model of Alzheimer's Disease Based on Differentiated Induced Pluripotent Stem Cells.

paper Cited Public

Authors: Lee, Han-Kyu; Velazquez Sanchez, Clara; Chen, Mei; Morin, Peter J; Wells, John M; Hanlon, Eugene B; Xia, Weiming
Year: 2016
Journal: PloS one
PMID: 27684569
DOI: 10.1371/journal.pone.0163072
PMCID: PMC5042502

Fig 1

Characterization of neural stem cells by protein markers Nestin and Sox2.Induced pluripotent stem cell-derived neural stem cells were identified by different protein markers, Nestin (green) and Sox2 (red). All 5 AD patients’ iPSC-derived neural stem cells were Nestin- and Sox2-immunoreactive. The expression of both protein markers was higher in N3 and N4 and lower in N1 and N5. Merged images are illustrated in yellow. Scale bar: 100 μm.

Fig 2

Characterization of neural stem cells by protein markers Sox1 and PAX6.iPSC-derived neural stem cells were identified by different protein markers, Sox1 (green) and PAX6 (red). Sox1 and PAX6 expression was higher in lines N3 and N4 compared to lines N1, N2 and N5. Merged images are illustrated in yellow. Scale bar: 50 μm.

Fig 3

Characterization of 2D neuronal culture differentiated from neural stem cells.2D neurons were immunostained with antibodies against the markers NeuN, GFAP, BT3 and MAP2. Differentiated neurons from all five subjects showed NeuN-, BT3- and MAP2-positive cells. Cells positive for the astrocyte marker GFAP were also presented. The left column of images is an illustration of merged NeuN (red) and GFAP (green) staining. NeuN (red) is highly expressed in the nucleus of differentiated neurons whereas GFAP (green) is expressed in the filament of the astrocytes. Nuclei staining was illustrated in blue across all images. Scale bar: 100 μm.

Fig 4

Characterization of 3D neuro-spheroid cultures by NeuN and GFAP.Neuro-spheroids (3DS1-5) were characterized by immunofluorescence staining of different protein markers, NeuN (green) and GFAP (red). Neuro-spheroids were positive for both NeuN and GFAP in all 5 cell lines. Merged and magnified images illustrate NeuN positive nucleus (green) and GFAP positive cells (red) localized in the filaments of astrocytes. Representative bright field (BF) images are presented on the left column. Scale bar: 50 μm.

Fig 5

Characterization of 3D neuro-spheroid cultures by MAP2 and PAX6.Neuro-spheroids (3DS1-5) were characterized by immunofluorescence staining of different marker proteins MAP2 (green) and PAX6 (red). All cells are immunoreactive to neuronal marker MAP2. Because the neuro-spheroids were still undergoing differentiation at the time of the immunostaining, some cells were found immune-positive with early neuronal differentiation marker PAX6. Merged and magnified images showed different distribution of both cell types. Bright field (BF) images are represented in the left column. Scale bar: 50 μm.

Fig 6

Structures of the BACE1 and γ-secretase inhibitors used to treat 3D neurons.A. Immunocytochemical staining of 3D neuro-spheroid section for Tau protein using antibody BT-2. B. ICC of neuro-spheroid section for phosphorylated Tau. Antibody AT270 specifically stains phosphor-Tau at residue Thr181. C. LY2886721, a potent and selective BACE1 inhibitor (left), and Compound E, a cell permeable non-competitive inhibitor of γ-secretase (right), are used to treat neurons.

Fig 7

Treatment of 2D cell culture by a γ-secretase inhibitor.2D neurons differentiated from five AD patients’ iPSC lines were treated with increasing concentrations of γ-secretase inhibitor (g-SI, 0.1, 0.5 and 1 μM; red) or DMSO as control (grey). A. Aβ40 levels in conditioned media from cells treated with γ-secretase inhibitor were significantly reduced. B. Aβ42 levels were significantly decreased in all 5 AD subjects after treatment with the γ-secretase inhibitor at all doses tested. The graph shows Mean±standard error of means (SEM); * represents p< 0.05, comparison of inhibitor vs. DMSO.

Fig 8

Treatment of 2D cell culture by a BACE1 inhibitor.2D neurons differentiated from five AD patients’ iPSC lines were treated with increasing concentrations of BACE1 inhibitor (BI, 0.1, 0.5 and 1 μM; blue) or DMSO as control (grey) for two days. Conditioned media were collected and Aß 40 and 42 were quantified by ELISA. Both Aß 40 (A) and 42 (B) levels were significantly reduced in all lines from 5 AD subjects after the treatment with the BACE inhibitor at all doses tested. Levels of Aβ42 were undetectable in 1 μM BI-treated neurons derived from AD5. The graph shows Mean±SEM; * represents p< 0.05, comparison of inhibitor vs. DMSO.

Fig 9

Treatment of 3D neuro-spheroids with BACE1 and γ-secretase inhibitors.3D neuro-spheroids differentiated from five AD patients’ iPSC lines were treated with either BACE1 (BI, 1 μM; blue) or γ-secretase inhibitor (g-SI, 0.5 or 1 μM; red) for two days. Media were collected for Aß 40 (top) and 42 (middle) ELISA quantification. A. Lower levels of Aß 40 were found in media after treatment with either BACE1 or γ-secretase inhibitors. B. Aß42 levels from AD1 remained unchanged after being exposed to BACE1 inhibitor. Aβ42 levels from other AD subjects were reduced. C. The drug levels of BACE1 inhibitor (blue, dosing at 1 μM) and γ-secretase inhibitor (red, dosing at 1 μM) in 3D neuro-spheroids were quantified by LC-MS/MS. The graph shows Mean±SEM; * represents p< 0.05, comparison of inhibitor vs. DMSO.

#	Section	Preview
40	Discussion	The uniqueness of using iPSC-differentiated neurons is obvious by the variation among the five lines…
41	Discussion	mutation at the BACE1 cleavage site [40], increases the expression levels of several genes like APP…
42	Discussion	The individual variation may also relate to differential Aβ clearance in 2D and 3D systems.…
43	Discussion	Future studies are needed to understand the cell biology of 3D neuro-spheroids derived from iPSC and…

Name	Type
2D culture local	cohort
2D cultured cell system local	cohort
2D cultures local	cohort
2D neuronal culture local	cohort
2D neuronal cultures local	drug
2D neurons local	anatomy
3D neuronal culture local	cohort
3D neuronal spheroids local	cohort
3D neuron cells local	anatomy
3D neuro-spheroid local	drug
3D neuro-spheroids local	cohort
3D neuro-spheroids local	drug
3D spheroids local	drug
6E10 antibody local	drug
accutase	drug
acetonitrile local	drug
AD1 local	cohort
AD1 subject local	cohort
AD2 local	cohort
AD2-5 local	cohort
AD3 local	cohort
AD4 local	cohort
AD5 local	cohort
Adaptor Protein 2 local	gene
AD patients	cohort
AD subjects	cohort
advanced dementia local	phenotype
Alzheimer's disease	phenotype
Amyloid beta	drug
Amyloid-beta	drug
Amyloid beta 1-40 local	drug
Amyloid beta 1-42 local	drug
Amyloid-beta peptide	drug
amyloid reduction local	phenotype
amyloid β local	phenotype
anti-amyloid therapeutics local	drug
antibody AT270 local	drug
antibody BT-2 local	drug
apoE	gene
APP	gene
APP C-terminal fragment local	drug
APP-E693Δ local	variant
Aβ local	phenotype
Aβ1-40 local	drug
Aβ 40 local	phenotype
Aβ40 local	drug
Aβ40 local	phenotype
Aβ 42 local	phenotype
Aβ42 local	drug
Aβ42 local	phenotype
Aβ42/Aβ40 ratio	phenotype
Aβ clearance	phenotype
Aβ levels	phenotype
B-27 serum substitute local	drug
B27 supplement	drug
Bace1	gene
BACE1 cleavage site mutation local	variant
BACE1 inhibitor local	drug
BACE1 inhibitors local	drug
basic fibroblast growth factor	drug
Bdnf	gene
Bedford VA Hospital local	cohort
bovine serum albumin	drug
C18 reverse-phase capillary column local	drug
C18 tips local	drug
candidate drugs local	drug
carbamidomethyl local	drug
cellular responses local	phenotype
cellular responsivity local	phenotype
centenarians	cohort
chronic dosing local	phenotype
Clathrin local	gene
clathrin proteins local	gene
compound E	drug
control cognitively normal centenarians local	cohort
cortex	anatomy
CytoTune-iPS Sendai Reprogramming Kit local	drug
dementia	phenotype
Dementia Special Care Unit (GRECC) local	cohort
DHA	drug
drug	drug
drug efficacy	phenotype
drug exposure	phenotype
drug metabolism	phenotype
drug screening local	phenotype
drug treatment	drug
dry ice	drug
E8 medium local	drug
early-onset autosomal recessive familial AD patients local	cohort
early-stage cognitive deficits local	phenotype
EGF	drug
embedding-medium local	drug
entorhinal cortex	anatomy
ER stress local	phenotype
ESI spray voltage local	drug
executive function	phenotype
FGF2	drug
five subjects local	cohort
fluorophores local	drug
formic acid	drug
Gamma-secretase local	gene
Geltrex matrix local	drug
genetic markers local	phenotype
GFAP	gene
GFAP antibody	drug
Glutamax	drug
GRECC Dementia Special Care Unit local	cohort
GSK3B	gene
high throughput screening local	phenotype
HPLC system local	drug
induced pluripotent stem cells	drug
inhibitors local	drug
intraneuronal Tau accumulation local	phenotype
iodoacetamide local	drug
iPSC colonies local	cohort
iPSC-derived neuro-spheroids local	drug
iPSC-differentiated cells local	drug
Klf4	gene
laminin	drug
language	phenotype
limbic system	anatomy
LY2886721 local	drug
MAP2	gene
MAP2 antibody local	drug
Mapt	gene
Microtubules local	phenotype
Mouse embryonic fibroblasts local	drug
Myc	gene
nano-ES ion source local	drug
neocortex	anatomy
neocortical regions	anatomy
NES	gene
Nestin antibody local	drug
NeuN	drug
NeuN antibody local	drug
neural expansion medium local	drug
neural induction medium local	drug
neural medium local	drug
neural stem cells	cohort
neuritic plaques	phenotype
Neurobasal	drug
neurobasal medium	drug
neurofibrillary tangles	phenotype
neuroinflammation	phenotype
neuronal differentiation	phenotype
neuronal loss	phenotype
neurons	phenotype
neuro-spheroids local	anatomy
neuro-spheroids local	cohort
normal controls	cohort
normal goat serum	drug
NT3	drug
Oct4	gene
oxidation local	drug
paraformaldehyde	drug
Pax6	gene
PAX6 local	drug
PAX6 antibody local	drug
penicillin	drug
Peripheral blood mononuclear cells local	drug
PET scan local	drug
phosphorylated tau	drug
PMBC medium local	drug
poly-l-ornithine	drug
Primary neuronal cultures local	cohort
PSEN1	gene
PSEN2	gene
pTau181 local	phenotype
pTau181 antibody AT270 local	drug
pTau Thr231 local	phenotype
Q Exactive Orbitrap MS local	drug
RBFOX3	gene
reduced drug exposure local	phenotype
reduced efficacy local	phenotype
ROCK	gene
sAD1 local	cohort
sAD2 local	cohort
saturation of inhibition local	phenotype
Sendai virus particles local	drug
Sendai virus protein local	drug
smooth muscle actin local	phenotype
SNP	cohort
SOX1	gene
Sox1 antibody local	drug
Sox2	gene
Sox2 antibody local	drug
spatial ability	phenotype
streptomycin	drug
sucrose solution	drug
Swedish mutation	variant
synapse loss	phenotype
Tandem mass tag 6-plex reagents local	drug
tau	phenotype
Tau antibody BT-2 local	drug
Tau oligomers local	drug
tau protein	drug
temporal lobe	anatomy
terminal differentiation local	phenotype
therapeutic applications local	drug
Thermo Fisher Scientific	drug
Thermo Xcalibur 3.0.63 local	drug
thiazovivin	drug
TMT/+ 229D-K local	drug
TMT/+ 229D-N Terminal local	drug
TMT labelled peptides local	drug
TRA-1-60	phenotype
TRA-1-81	phenotype
tris(2-carboxyethyl)phosphine local	drug
Triton X-100	drug
trypsin	drug
TUBB3	gene
ultra-low-attachment plastic plates local	drug
variable drug bioavailability local	phenotype
Visual ability local	phenotype
Yamanaka factors local	gene
α-fetoprotein local	phenotype
β-III tubulin local	phenotype
β tubulin III local	drug
β tubulin III antibody local	drug
γ-secretase	drug
γ-secretase inhibitor	drug

Citation	PMID	DOI	Status
ArriagadaPV, GrowdonJH, Hedley-WhyteET, HymanBT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992;42(3 Pt 1):631–9. .154922810.1212/wnl.42.3.631	—	—	—
BaulacS, LuH, StrahleJ, YangT, GoldbergMS, ShenJ, et al Increased DJ-1 expression under oxidative stress and in Alzheimer's disease brains. Mol Neurodegener. 2009;4(12):12 10.1186/1750-1326-4-12 .19243613PMC2654450	—	—	—
BraakH, Del TrediciK. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta neuropathologica. 2011;121(2):171–81. 10.1007/s00401-010-0789-4 .21170538	—	—	—
CallaertsP, HalderG, GehringWJ. PAX-6 in development and evolution. Annu Rev Neurosci. 1997;20:483–532. Epub 1997/01/01. 10.1146/annurev.neuro.20.1.483 .9056723	—	—	—
ChoiSH, KimYH, HebischM, SliwinskiC, LeeS, D'AvanzoC, et al A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014;515(7526):274–8. Epub 2014/10/14 06:00. 10.1038/nature1380025307057PMC4366007	—	—	—
ChouBK, MaliP, HuangX, YeZ, DoweySN, ResarLM, et al Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res. 2011;21(3):518–29. 10.1038/cr.2011.1221243013PMC3193421	—	—	—
CitronM, OltersdorfT, HaassC, McConlogueL, HungAY, SeubertP, et al Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992;360(6405):672–4. 10.1038/360672a0 .1465129	—	—	—
CrystalHA, DicksonDW, SliwinskiMJ, LiptonRB, GroberE, Marks-NelsonH, et al Pathological markers associated with normal aging and dementia in the elderly. Annals of neurology. 1993;34(4):566–73. 10.1002/ana.410340410 .8215244	—	—	—
EllisP, FaganBM, MagnessST, HuttonS, TaranovaO, HayashiS, et al SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev Neurosci. 2004;26(2–4):148–65. Epub 2005/02/16. 10.1159/000082134 .15711057	—	—	—
Gomez-LopezS, WiskowO, FavaroR, NicolisSK, PriceDJ, PollardSM, et al Sox2 and Pax6 maintain the proliferative and developmental potential of gliogenic neural stem cells In vitro. Glia. 2011;59(11):1588–99. Epub 2011/07/19. 10.1002/glia.21201 .21766338	—	—	—
GueretteD, KhanPA, SavardPE, VincentM. Molecular evolution of type VI intermediate filament proteins. BMC Evol Biol. 2007;7:164 Epub 2007/09/15. 10.1186/1471-2148-7-164 17854500PMC2075511	—	—	—
IsraelMA, YuanSH, BardyC, ReynaSM, MuY, HerreraC, et al Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012;482(7384):216–20. 10.1038/nature1082122278060PMC3338985	—	—	—
KondoT, AsaiM, TsukitaK, KutokuY, OhsawaY, SunadaY, et al Modeling Alzheimer's Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Abeta and Differential Drug Responsiveness. Cell Stem Cell. 2013;5909(13):009 10.1016/j.stem.2013.01.009 .23434393	—	—	—
LeeHK, MorinP, XiaW. Peripheral blood mononuclear cell-converted induced pluripotent stem cells (iPSCs) from an early onset Alzheimer’s patient. Stem Cell Research. 2016;16(2):213–5. 10.1016/j.scr.2015.12.050 27345971PMC7008971	—	—	—
LeeMK, TuttleJB, RebhunLI, ClevelandDW, FrankfurterA. The expression and posttranslational modification of a neuron-specific beta-tubulin isotype during chick embryogenesis. Cell Motil Cytoskeleton. 1990;17(2):118–32. Epub 1990/01/01. 10.1002/cm.970170207 .2257630	—	—	—
LieuPT, FontesA, VemuriMC, MacarthurCC. Generation of induced pluripotent stem cells with CytoTune, a non-integrating Sendai virus. Methods Mol Biol. 2013;997:45–56. 10.1007/978-1-62703-348-0_523546747	—	—	—
MayPC, WillisBA, LoweSL, DeanRA, MonkSA, CockePJ, et al The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015;35(3):1199–210. Epub 2015/01/23 06:00. 10.1523/JNEUROSCI.4129-14.201525609634PMC6605527	—	—	—
McKeeAC, KosikKS, KowallNW. Neuritic pathology and dementia in Alzheimer's disease. Annals of neurology. 1991;30(2):156–65. 10.1002/ana.410300206 .1910274	—	—	—
MichalczykK, ZimanM. Nestin structure and predicted function in cellular cytoskeletal organisation. Histol Histopathol. 2005;20(2):665–71. Epub 2005/03/01. .1573606810.14670/HH-20.665	—	—	—
MullenRJ, BuckCR, SmithAM. NeuN, a neuronal specific nuclear protein in vertebrates. Development. 1992;116(1):201–11. Epub 1992/09/01. .148338810.1242/dev.116.1.201	—	—	—
NelsonPT, BraakH, MarkesberyWR. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. Journal of neuropathology and experimental neurology. 2009;68(1):1–14. 10.1097/NEN.0b013e3181919a48 19104448PMC2692822	—	—	—
NelsonPT, JichaGA, SchmittFA, LiuH, DavisDG, MendiondoMS, et al Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles "do count" when staging disease severity. Journal of neuropathology and experimental neurology. 2007;66(12):1136–46. 10.1097/nen.0b013e31815c5efb 18090922PMC3034246	—	—	—
PascaAM, SloanSA, ClarkeLE, TianY, MakinsonCD, HuberN, et al Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015;12(7):671–8. 10.1038/nmeth.3415 26005811PMC4489980	—	—	—
PoulsenET, LarsenA, ZolloA, JorgensenAL, SanggaardKW, EnghildJJ, et al New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies. Int J Mol Sci. 2015;16(12):29446–53. Epub 2015/12/23 06:00. 10.3390/ijms16122618126690411PMC4691124	—	—	—
QuerfurthHW, LaFerlaFM. Alzheimer's disease. N Engl J Med. 2010;362(4):329–44. 10.1056/NEJMra0909142 .20107219	—	—	—
RileyKP, JichaGA, DavisD, AbnerEL, CooperGE, StilesN, et al Prediction of preclinical Alzheimer's disease: longitudinal rates of change in cognition. Journal of Alzheimer's disease: JAD. 2011;25(4):707–17. 10.3233/JAD-2011-102133 21498903PMC3353267	—	—	—
SansomSN, GriffithsDS, FaedoA, KleinjanDJ, RuanY, SmithJ, et al The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet. 2009;5(6):e1000511 Epub 2009/06/13. 10.1371/journal.pgen.1000511 19521500PMC2686252	—	—	—
SchmittFA, DavisDG, WeksteinDR, SmithCD, AshfordJW, MarkesberyWR. "Preclinical" AD revisited: neuropathology of cognitively normal older adults. Neurology. 2000;55(3):370–6. .1093227010.1212/wnl.55.3.370	—	—	—
SelkoeDJ. Alzheimer's disease is a synaptic failure. Science. 2002;298(5594):789–91. 10.1126/science.1074069 .12399581	—	—	—
SoltaniMH, PichardoR, SongZ, SanghaN, CamachoF, SatyamoorthyK, et al Microtubule-associated protein 2, a marker of neuronal differentiation, induces mitotic defects, inhibits growth of melanoma cells, and predicts metastatic potential of cutaneous melanoma. Am J Pathol. 2005;166(6):1841–50. Epub 2005/05/28 09:00. 10.1016/S0002-9440(10)62493-5 .15920168PMC1602405	—	—	—
TakahashiK, TanabeK, OhnukiM, NaritaM, IchisakaT, TomodaK, et al Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. Epub 2007/11/24 09:00. 10.1016/j.cell.2007.11.019 .18035408	—	—	—
ThalDR, RubU, OrantesM, BraakH. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791–800. .1208487910.1212/wnl.58.12.1791	—	—	—
TianY, ChangJC, FanEY, FlajoletM, GreengardP. 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. 2013;110(42):17071–6. Epub 2013/09/27 06:00. 10.1073/pnas.131511011024067654PMC3801056	—	—	—
TomlinsonBE, BlessedG, RothM. Observations on the brains of demented old people. Journal of the neurological sciences. 1970;11(3):205–42. .550568510.1016/0022-510x(70)90063-8	—	—	—
UsenovicM, NiroomandS, DroletRE, YaoL, GasparRC, HatcherNG, et al Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells. J Neurosci. 2015;35(42):14234–50. Epub 2015/10/23 06:00. 10.1523/JNEUROSCI.1523-15.201526490863PMC6605424	—	—	—
van der ZeeJ, SleegersK, Van BroeckhovenC. Invited article: the Alzheimer disease-frontotemporal lobar degeneration spectrum. Neurology. 2008;71(15):1191–7. 10.1212/01.wnl.0000327523.52537.86 .18838666	—	—	—
VenereM, HanYG, BellR, SongJS, Alvarez-BuyllaA, BlellochR. Sox1 marks an activated neural stem/progenitor cell in the hippocampus. Development. 2012;139(21):3938–49. Epub 2012/09/21. 10.1242/dev.081133 22992951PMC3472585	—	—	—
XiaW, ZhangJ, KholodenkoD, CitronM, PodlisnyMB, TeplowDB, et al Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J Biol Chem. 1997;272(12):7977–82. .906546810.1074/jbc.272.12.7977	—	—	—
YagiT, ItoD, OkadaY, AkamatsuW, NiheiY, YoshizakiT, et al Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet. 2011;20(23):4530–9. 10.1093/hmg/ddr39421900357	—	—	—
YangT, ArslanovaD, GuY, Augelli-SzafranC, XiaW. Quantification of gamma-secretase modulation differentiates inhibitor compound selectivity between two substrates Notch and amyloid precursor protein. Mol Brain. 2008;1(1):15 10.1186/1756-6606-1-15 .18983676PMC2637266	—	—	—

In this knowledge base

Title	Year	PMID
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	2018	29897633

External

Title	Authors	Journal	Year	Link
Exploring prodrug approaches for Alzheimer's treatment: an overview.	Kumari P et al.	—	2026	→
3D Printing for Neural Repair: Bridging the Gap in Regenerative Medicine.	St Clair-Glover M et al.	—	2025	→
Cell and tissue reprogramming: Unlocking a new era in medical drug discovery.	Sen CK et al.	—	2025	→
Chipless Millifluidics Device for Rapid Fabrication of Hepatic Spheroids with Decellularized Liver Matrix.	Ghosh S et al.	—	2025	→
Geometrical constraints dictate assembly and phenotype of human iPSC-derived motoneuronal spheroids.	Mello E et al.	—	2025	→
Implementing a trilineage differentiation in the ReproTracker assay for improved teratogenicity assessment.	Horcas-Nieto JM et al.	—	2025	→
Lithium deficiency and the onset of Alzheimer's disease.	Aron L et al.	—	2025	→
Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier.	Shamul JG et al.	—	2025	→
Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.	Kuhn MK et al.	—	2025	→
Modeling Alzheimer's Disease: A Review of Gene-Modified and Induced Animal Models, Complex Cell Culture Models, and Computational Modeling.	Timofeeva AM et al.	—	2025	→
One-Step Drug Screening System Utilizing Electrophysiological Activity in Multiple Brain Organoids.	Shin H et al.	—	2025	→
Self-assembly and 3D Bioprinting of Neurospheres and Evaluation of Caffeine and Photobiomodulation Effects in an Alzheimer's Disease In Vitro Model.	Rodrigues Salles G et al.	—	2025	→
Approaches for studying neuroimmune interactions in Alzheimer's disease.	Lin C' et al.	—	2024	→
Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.	Briglia M et al.	—	2024	→
Disease Modifying Monoclonal Antibodies and Symptomatic Pharmacological Treatment for Alzheimer's Disease.	Qi X et al.	—	2024	→
Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration.	Birkle TJY et al.	—	2024	→
Human midbrain organoids: a powerful tool for advanced Parkinson's disease modeling and therapy exploration.	Cui X et al.	—	2024	→
Modeling Alzheimer's disease using human cell derived brain organoids and 3D models.	Fernandes S et al.	—	2024	→
Modeling the neuroimmune system in Alzheimer's and Parkinson's diseases.	Balestri W et al.	—	2024	→
Neuropathological changes in the TASTPM mouse model of Alzheimer's disease and their relation to hyperexcitability and cortical spreading depolarization.	Gimeno-Ferrer F et al.	—	2024	→
Simple modeling of familial Alzheimer's disease using human pluripotent stem cell-derived cerebral organoid technology.	Choe MS et al.	—	2024	→
3D bioprinting patient-derived induced pluripotent stem cell models of Alzheimer's disease using a smart bioink.	Benwood C et al.	—	2023	→
Advances in current <i>in vitro</i> models on neurodegenerative diseases.	Pereira I et al.	—	2023	→
An update on stem cell and stem cell-derived extracellular vesicle-based therapy in the management of Alzheimer's disease.	Jeyaraman M et al.	—	2023	→
A three-dimensional spheroid co-culture system of neurons and astrocytes derived from Alzheimer's disease patients for drug efficacy testing.	Park H et al.	—	2023	→
Current progress of cerebral organoids for modeling Alzheimer's disease origins and mechanisms.	Sreenivasamurthy S et al.	—	2023	→
Effects of Rhazya Stricta plant organic extracts on human induced pluripotent stem cells derived neural stem cells.	Alawad AO et al.	—	2023	→
In Vitro 3D Modeling of Neurodegenerative Diseases.	Louit A et al.	—	2023	→
Reduction of Phosphorylated Tau in Alzheimer's Disease Induced Pluripotent Stem Cell-Derived Neuro-Spheroids by Rho-Associated Coiled-Coil Kinase Inhibitor Fasudil.	Giunti E et al.	—	2023	→
Simple modeling of Alzheimer’s disease using human pluripotent stem cell-derived cerebral organoid technology	Choe MS et al.	—	2023	—
Spheroid Engineering in Microfluidic Devices.	Tevlek A et al.	—	2023	→
Successful 3D imaging of cleared biological samples with light sheet fluorescence microscopy.	Delage E et al.	—	2023	→
The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models.	Hebisch M et al.	—	2023	→
The Multifaceted Role of WNT Signaling in Alzheimer's Disease Onset and Age-Related Progression.	Kostes WW et al.	—	2023	→
Use of <i>in vitro</i> derived human neuronal models to study host-parasite interactions of <i>Toxoplasma gondii</i> in neurons and neuropathogenesis of chronic toxoplasmosis.	Halonen SK	—	2023	→
3D Neural Network Composed of Neurospheroid and Bionanohybrid on Microelectrode Array to Realize the Spatial Input Signal Recognition in Neurospheroid.	Yoon J et al.	—	2022	→
A 3D-induced pluripotent stem cell-derived human neural culture model to study certain molecular and biochemical aspects of Alzheimer's disease.	Prasannan P et al.	—	2022	→
Advances in stromal cell therapy for management of Alzheimer's disease.	Srivastava R et al.	—	2022	→
Alzheimer's Disease: Treatment Strategies and Their Limitations.	Passeri E et al.	—	2022	→
Brain organoids: Establishment and application.	Chen H et al.	—	2022	→
Generation of iPSC-Derived Brain Organoids for Drug Testing and Toxicological Evaluation.	Nguyen HN	—	2022	→
High throughput 3D gel-based neural organotypic model for cellular assays using fluorescence biosensors.	Kundu S et al.	—	2022	→
Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol.	Glasauer SMK et al.	—	2022	→
Impact of the Flavonoid Quercetin on β-Amyloid Aggregation Revealed by Intrinsic Fluorescence.	Alghamdi A et al.	—	2022	→
Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer's disease.	Venkataraman L et al.	—	2022	→
Neurotechnological Approaches to the Diagnosis and Treatment of Alzheimer's Disease.	Ning S et al.	—	2022	→
Promising Strategies for the Development of Advanced In Vitro Models with High Predictive Power in Ischaemic Stroke Research.	Van Breedam E et al.	—	2022	→
Regionally defined proteomic profiles of human cerebral tissue and organoids reveal conserved molecular modules of neurodevelopment.	Melliou S et al.	—	2022	→
Repair, regeneration and rejuvenation require un-entangling pluripotency from senescence.	Tabibzadeh S	—	2022	→
Research models of neurodevelopmental disorders: The right model in the right place.	Damianidou E et al.	—	2022	→
Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model.	Rickner HD et al.	—	2022	→
Synaptic dysfunction in early phases of Alzheimer's Disease.	Pelucchi S et al.	—	2022	→
The promise of organoids for unraveling the proteomic landscape of the developing human brain.	Melliou S et al.	—	2022	→
A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies.	Kang Y et al.	—	2021	→
Alzheimer's Disease: Current Perspectives and Advances in Physiological Modeling.	Josephine Boder E et al.	—	2021	→
Brain Organoids: Tiny Mirrors of Human Neurodevelopment and Neurological Disorders.	Yadav A et al.	—	2021	→
Deconstructing Alzheimer's Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?	Vignon A et al.	—	2021	→
Emerging Brain-Pathophysiology-Mimetic Platforms for Studying Neurodegenerative Diseases: Brain Organoids and Brains-on-a-Chip.	Bang S et al.	—	2021	→
Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases.	Trudler D et al.	—	2021	→
From Brain Organoids to Networking Assembloids: Implications for Neuroendocrinology and Stress Medicine.	Makrygianni EA et al.	—	2021	→
High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases.	Aldewachi H et al.	—	2021	→
Human mini-brain models.	Tan HY et al.	—	2021	→
Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer's Disease.	Ryu WI et al.	—	2021	→
The ECM: To Scaffold, or Not to Scaffold, That Is the Question.	Valdoz JC et al.	—	2021	→
Toward three-dimensional <i>in vitro</i> models to study neurovascular unit functions in health and disease.	Caffrey TM et al.	—	2021	→
4D Self-Morphing Culture Substrate for Modulating Cell Differentiation.	Miao S et al.	—	2020	→
A microfiber scaffold-based 3D in vitro human neuronal culture model of Alzheimer's disease.	Ranjan VD et al.	—	2020	→
Challenges in Physiological Phenotyping of hiPSC-Derived Neurons: From 2D Cultures to 3D Brain Organoids.	Mateos-Aparicio P et al.	—	2020	→
Gaining New Biological and Therapeutic Applications into the Liver with 3D In Vitro Liver Models.	Lee SW et al.	—	2020	→
If Human Brain Organoids Are the Answer to Understanding Dementia, What Are the Questions?	Ooi L et al.	—	2020	→
<i>In vitro</i> Models of Neurodegenerative Diseases.	Slanzi A et al.	—	2020	→
Innovations in 3-Dimensional Tissue Models of Human Brain Physiology and Diseases.	Lovett ML et al.	—	2020	→
Modelling frontotemporal dementia using patient-derived induced pluripotent stem cells.	Lines G et al.	—	2020	→
Pluripotent stem cells for neurodegenerative disease modeling: an expert view on their value to drug discovery.	Chen SD et al.	—	2020	→
Retinal and Brain Organoids: Bridging the Gap Between <i>in vivo</i> Physiology and <i>in vitro</i> Micro-Physiology for the Study of Alzheimer's Diseases.	Brighi C et al.	—	2020	→
Sowing the Seeds of Discovery: Tau-Propagation Models of Alzheimer's Disease.	Bell BJ et al.	—	2020	→
Synergy between amyloid-β and tau in Alzheimer's disease.	Busche MA et al.	—	2020	→
Three-dimensional modeling of human neurodegeneration: brain organoids coming of age.	Grenier K et al.	—	2020	→
Three-Dimensional Models for Studying Neurodegenerative and Neurodevelopmental Diseases.	Tsaridou S et al.	—	2020	→
A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration.	Ubina T et al.	—	2019	→
Alzheimer's in a dish - induced pluripotent stem cell-based disease modeling.	de Leeuw S et al.	—	2019	→
Assessing drug response in engineered brain microenvironments.	Tate KM et al.	—	2019	→
Drugs for Targeted Therapies of Alzheimer's Disease.	Tam C et al.	—	2019	→
Human iPSC application in Alzheimer's disease and Tau-related neurodegenerative diseases.	Tcw J	—	2019	→
Human iPS Cell-Derived Patient Tissues and 3D Cell Culture Part 2: Spheroids, Organoids, and Disease Modeling.	Eglen RM et al.	—	2019	→
Induced pluripotent stem cells for neural drug discovery.	Farkhondeh A et al.	—	2019	→
Integrated Microphysiological Systems: Transferable Organ Models and Recirculating Flow.	Renggli K et al.	—	2019	→
Modelling mitochondrial dysfunction in Alzheimer's disease using human induced pluripotent stem cells.	Hawkins KE et al.	—	2019	→
Opportunities and challenges for the use of induced pluripotent stem cells in modelling neurodegenerative disease.	Wu YY et al.	—	2019	→
Recent Expansions on Cellular Models to Uncover the Scientific Barriers Towards Drug Development for Alzheimer's Disease.	Dubey SK et al.	—	2019	→
Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models.	Logan S et al.	—	2019	→
Targeting the ensemble of heterogeneous tau oligomers in cells: A novel small molecule screening platform for tauopathies.	Lo CH et al.	—	2019	→
The Use of Pluripotent Stem Cell-Derived Organoids to Study Extracellular Matrix Development during Neural Degeneration.	Yan Y et al.	—	2019	→
2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling.	Centeno EGZ et al.	—	2018	→
Common proteomic profiles of induced pluripotent stem cell-derived three-dimensional neurons and brain tissue from Alzheimer patients.	Chen M et al.	—	2018	→
Forced differentiation in vitro leads to stress-induced activation of DNA damage response in hiPSC-derived chondrocyte-like cells.	Stelcer E et al.	—	2018	→
Generation of high-yield insulin producing cells from human-induced pluripotent stem cells on polyethersulfone nanofibrous scaffold.	Mansour RN et al.	—	2018	→
Generation of insulin-producing cells from human induced pluripotent stem cells on PLLA/PVA nanofiber scaffold.	Enderami SE et al.	—	2018	→
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	Prytkova I et al.	—	2018	→
Genome engineering for CNS injury and disease.	Pardieck J et al.	—	2018	→
Human Neurospheroid Arrays for In Vitro Studies of Alzheimer's Disease.	Jorfi M et al.	—	2018	→
Induced pluripotent stem cells as a tool to study brain circuits in autism-related disorders.	Vitrac A et al.	—	2018	→
Materials for Neural Differentiation, Trans-Differentiation, and Modeling of Neurological Disease.	Gong L et al.	—	2018	→
Modeling Neurodegenerative Microenvironment Using Cortical Organoids Derived from Human Stem Cells.	Yan Y et al.	—	2018	→
Modeling Neurological Diseases With Human Brain Organoids.	Wang H	—	2018	→
Modelling Alzheimer's disease: Insights from in vivo to in vitro three-dimensional culture platforms.	Ranjan VD et al.	—	2018	→
Modelling Sporadic Alzheimer's Disease Using Induced Pluripotent Stem Cells.	Rowland HA et al.	—	2018	→
Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the A<i>β</i>42-Treated Forebrain Spheroids Derived from Human Stem Cells.	Bejoy J et al.	—	2018	→
Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau.	Chen M et al.	—	2018	→
Recent Advances: Decoding Alzheimer's Disease With Stem Cells.	Fang Y et al.	—	2018	→
Representing Diversity in the Dish: Using Patient-Derived <i>in Vitro</i> Models to Recreate the Heterogeneity of Neurological Disease.	Ghaffari LT et al.	—	2018	→
Three-Dimensional Models of the Human Brain Development and Diseases.	Jorfi M et al.	—	2018	→
Closed-channel culture system for efficient and reproducible differentiation of human pluripotent stem cells into islet cells.	Hirano K et al.	—	2017	→
Generating CNS organoids from human induced pluripotent stem cells for modeling neurological disorders.	Brawner AT et al.	—	2017	→
Generation of Insulin-Producing Cells From Human-Induced Pluripotent Stem Cells Using a Stepwise Differentiation Protocol Optimized With Platelet-Rich Plasma.	Enderami SE et al.	—	2017	→
Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation.	Caldeira C et al.	—	2017	→
Microdevice Platform for In Vitro Nervous System and Its Disease Model.	Choi JH et al.	—	2017	→
Stem cell models of Alzheimer's disease: progress and challenges.	Arber C et al.	—	2017	→
3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish".	Choi SH et al.	—	2016	→