BACKGROUND: Synaptic dysfunction is a major contributor to Alzheimeŕs disease (AD) pathogenesis in addition to the formation of neuritic β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau protein. However, how these features contribute to synaptic dysfunction and axonal loss remains unclear. While years of considerable effort have been devoted to gaining an improved understanding of this devastating disease, the unavailability of patient-derived tissues, considerable genetic heterogeneity, and lack of animal models that faithfully recapitulate human AD have hampered the development of effective treatment options. Ongoing progress in human induced pluripotent stem cell (hiPSC) technology has permitted the derivation of patient- and disease-specific stem cells with unlimited self-renewal capacity. These cells can differentiate into AD-affected cell types, which support studies of disease mechanisms, drug discovery, and the development of cell replacement therapies in traditional and advanced cell culture models. AIM OF REVIEW: To summarize current hiPSC-based AD models, highlighting the associated achievements and challenges with a primary focus on neuron and synapse loss. KEY SCIENTIFIC CONCEPTS OF REVIEW: We aim to identify how hiPSC models can contribute to understanding AD-associated synaptic dysfunction and axonal loss. hiPSC-derived neural cells, astrocytes, and microglia, as well as more sophisticated cellular organoids, may represent reliable models to investigate AD and identify early markers of AD-associated neural degeneration.

Institute of Experimental Medicine Department of Neuroregeneration Czech Academy of Science Prague Czech Republic

Stem Cell Therapies in Neurodegenerative Diseases Lab Centro de Investigación Principe Felipe c Eduardo Primo Yúfera 3 46012 Valencia Spain

Stem Cell Therapies in Neurodegenerative Diseases Lab Centro de Investigación Principe Felipe c Eduardo Primo Yúfera 3 46012 Valencia Spain; Institute of Experimental Medicine Department of Neuroregeneration Czech Academy of Science Prague Czech Republic; National Stem Cell Bank Valencia Node Centro de Investigacion Principe Felipe c Eduardo Primo Yúfera 3 46012 Valencia Spain

See more in PubMed

Hort J., O'Brien J.T., Gainotti G., Pirttila T., Popescu B.O., Rektorova I., et al. EFNS guidelines for the diagnosis and management of Alzheimer's disease. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2010;17:1236–1248. PubMed

Frisoni G.B., Fox N.C., Jack C.R., Jr., Scheltens P., Thompson P.M. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol. 2010;6:67–77. PubMed PMC

S.J. Crutch, J.M. Schott, G.D. Rabinovici, M. Murray, J.S. Snowden, W.M. van der Flier, B.C. Dickerson, R. Vandenberghe, S. Ahmed, T.H. Bak, B.F. Boeve, C. Butler, S.F. Cappa, M. Ceccaldi, L.C. de Souza, B. Dubois, O. Felician, D. Galasko, J. Graff-Radford, N.R. Graff-Radford, P.R. Hof, P. Krolak-Salmon, M. Lehmann, E. Magnin, M.F. Mendez, P.J. Nestor, C.U. Onyike, V.S. Pelak, Y. Pijnenburg, S. Primativo, M.N. Rossor, N.S. Ryan, P. Scheltens, T.J. Shakespeare, A. Suarez Gonzalez, D.F. Tang-Wai, K.X.X. Yong, M. Carrillo, N.C. Fox, I.A.A.s.D. Alzheimer's Association, and A. Associated Syndromes Professional Interest, Consensus classification of posterior cortical atrophy. Alzheimers Dement 13 (2017) 870-884. PubMed PMC

Braak H., Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. PubMed

Selkoe D.J. The molecular pathology of Alzheimer's disease. Neuron. 1991;6:487–498. PubMed

Frost B., Jacks R.L., Diamond M.I. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–12852. PubMed PMC

Butterfield D.A., Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20:148–160. PubMed PMC

DeKosky S.T., Scheff S.W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–464. PubMed

Terry R.D., Masliah E., Salmon D.P., Butters N., DeTeresa R., Hill R., et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580. PubMed

Edwards F.A. A Unifying Hypothesis for Alzheimer's Disease: From Plaques to Neurodegeneration. Trends Neurosci. 2019;42:310–322. PubMed

Iacono D., O'Brien R., Resnick S.M., Zonderman A.B., Pletnikova O., Rudow G., et al. Neuronal hypertrophy in asymptomatic Alzheimer disease. J Neuropathol Exp Neurol. 2008;67:578–589. PubMed PMC

Sasaguri H., Nilsson P., Hashimoto S., Nagata K., Saito T., De Strooper B., et al. APP mouse models for Alzheimer's disease preclinical studies. EMBO J. 2017;36:2473–2487. PubMed PMC

Bateman R.J., Aisen P.S., De Strooper B., Fox N.C., Lemere C.A., Ringman J.M., et al. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimers Res Ther. 2011;3:1. PubMed PMC

Verghese P.B., Castellano J.M., Holtzman D.M. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 2011;10:241–252. PubMed PMC

Karch C.M., Goate A.M. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43–51. PubMed PMC

Kent S.A., Spires-Jones T.L., Durrant C.S. The physiological roles of tau and Abeta: implications for Alzheimer's disease pathology and therapeutics. Acta Neuropathol. 2020;140:417–447. PubMed PMC

Scearce-Levie K., Sanchez P.E., Lewcock J.W. Leveraging preclinical models for the development of Alzheimer disease therapeutics. Nat Rev Drug Discov. 2020;19:447–462. PubMed

Serrano-Pozo A., Frosch M.P., Masliah E., Hyman B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011;1 PubMed PMC

Fotuhi M., Hachinski V., Whitehouse P.J. Changing perspectives regarding late-life dementia. Nat Rev Neurol. 2009;5:649–658. PubMed

Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356. PubMed

Musiek E.S., Holtzman D.M. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci. 2015;18:800–806. PubMed PMC

Selkoe D.J., Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8:595–608. PubMed PMC

Hyman B.T. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol. 2011;68:1062–1064. PubMed

Holtzman D.M., Carrillo M.C., Hendrix J.A., Bain L.J., Catafau A.M., Gault L.M., et al. Tau: From research to clinical development. Alzheimers Dement. 2016;12:1033–1039. PubMed

Braak H., Braak E. Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol. 1990;49:215–224. PubMed

Nagy Z., Esiri M.M., Jobst K.A., Johnston C., Litchfield S., Sim E., et al. Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease. Neuroscience. 1995;69:757–761. PubMed

Abramov E., Dolev I., Fogel H., Ciccotosto G.D., Ruff E., Slutsky I. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009;12:1567–1576. PubMed

Puzzo D., Privitera L., Fa M., Staniszewski A., Hashimoto G., Aziz F., et al. Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory. Ann Neurol. 2011;69:819–830. PubMed PMC

Spires T.L., Meyer-Luehmann M., Stern E.A., McLean P.J., Skoch J., Nguyen P.T., et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005;25:7278–7287. PubMed PMC

Burgold S., Bittner T., Dorostkar M.M., Kieser D., Fuhrmann M., Mitteregger G., et al. In vivo multiphoton imaging reveals gradual growth of newborn amyloid plaques over weeks. Acta Neuropathol. 2011;121:327–335. PubMed PMC

Wu H.Y., Hudry E., Hashimoto T., Uemura K., Fan Z.Y., Berezovska O., et al. Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-beta revealed by a novel fluorescence resonance energy transfer assay. J Neurosci. 2012;32:5298–5309. PubMed PMC

Decker H., Jurgensen S., Adrover M.F., Brito-Moreira J., Bomfim T.R., Klein W.L., et al. N-methyl-D-aspartate receptors are required for synaptic targeting of Alzheimer's toxic amyloid-beta peptide oligomers. J Neurochem. 2010;115:1520–1529. PubMed

Birnbaum J.H., Bali J., Rajendran L., Nitsch R.M., Tackenberg C. Calcium flux-independent NMDA receptor activity is required for Abeta oligomer-induced synaptic loss. Cell Death Dis. 2015;6:e1791. PubMed PMC

Karran E., De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem. 2016;139(Suppl 2):237–252. PubMed

Wu H.Y., Kuo P.C., Wang Y.T., Lin H.T., Roe A.D., Wang B.Y., et al. beta-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals. J Neuropathol Exp Neurol. 2018;77:814–826. PubMed

Howlett D.R., Bowler K., Soden P.E., Riddell D., Davis J.B., Richardson J.C., et al. Abeta deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer's disease. Histol Histopathol. 2008;23:67–76. PubMed

Jack C.R., Jr., Bennett D.A., Blennow K., Carrillo M.C., Dunn B., Haeberlein S.B., et al. and Contributors, NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535–562. PubMed PMC

Zempel H., Luedtke J., Kumar Y., Biernat J., Dawson H., Mandelkow E., et al. Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013;32:2920–2937. PubMed PMC

Zempel H., Thies E., Mandelkow E., Mandelkow E.M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci. 2010;30:11938–11950. PubMed PMC

Rozkalne A., Hyman B.T., Spires-Jones T.L. Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiol Dis. 2011;41:650–654. PubMed PMC

Wu H.Y., Hudry E., Hashimoto T., Kuchibhotla K., Rozkalne A., Fan Z., et al. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010;30:2636–2649. PubMed PMC

Cohen R.M., Rezai-Zadeh K., Weitz T.M., Rentsendorj A., Gate D., Spivak I., et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci. 2013;33:6245–6256. PubMed PMC

Pooler A.M., Polydoro M., Wegmann S., Nicholls S.B., Spires-Jones T.L., Hyman B.T. Propagation of tau pathology in Alzheimer's disease: identification of novel therapeutic targets. Alzheimers Res Ther. 2013;5:49. PubMed PMC

Kashyap G., Bapat D., Das D., Gowaikar R., Amritkar R.E., Rangarajan G., et al. Synapse loss and progress of Alzheimer's disease -A network model. Sci Rep. 2019;9:6555. PubMed PMC

Pereira J.B., Janelidze S., Ossenkoppele R., Kvartsberg H., Brinkmalm A., Mattsson-Carlgren N., et al. Untangling the association of amyloid-beta and tau with synaptic and axonal loss in Alzheimer's disease. Brain. 2021;144:310–324. PubMed PMC

Allegra Mascaro A.L., Cesare P., Sacconi L., Grasselli G., Mandolesi G., Maco B., et al. In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex. Proc Natl Acad Sci U S A. 2013;110:10824–10829. PubMed PMC

Zhong L., Gerges N.Z. Neurogranin and synaptic plasticity balance. Commun Integr Biol. 2010;3:340–342. PubMed PMC

Danysz W., Parsons C.G. Alzheimer's disease, beta-amyloid, glutamate, NMDA receptors and memantine–searching for the connections. Br J Pharmacol. 2012;167:324–352. PubMed PMC

Sheline Y.I., Raichle M.E. Resting state functional connectivity in preclinical Alzheimer's disease. Biol Psychiatry. 2013;74:340–347. PubMed PMC

Huijbers W., Mormino E.C., Schultz A.P., Wigman S., Ward A.M., Larvie M., et al. Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain. 2015;138:1023–1035. PubMed PMC

Sepulcre J., Sabuncu M.R., Li Q., El Fakhri G., Sperling R., Johnson K.A. Tau and amyloid beta proteins distinctively associate to functional network changes in the aging brain. Alzheimers Dement. 2017;13:1261–1269. PubMed PMC

Spires-Jones T.L., Stoothoff W.H., de Calignon A., Jones P.B., Hyman B.T. Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci. 2009;32:150–159. PubMed

Oxford A.E., Stewart E.S., Rohn T.T. Clinical Trials in Alzheimer's Disease: A Hurdle in the Path of Remedy. Int J Alzheimers Dis. 2020;2020:5380346. PubMed PMC

Pascoal T.A., Benedet A.L., Ashton N.J., Kang M.S., Therriault J., Chamoun M., et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021;27:1592–1599. PubMed

Braak H., Braak E., Bohl J. Staging of Alzheimer-related cortical destruction. Eur Neurol. 1993;33:403–408. PubMed

Raichle M.E., MacLeod A.M., Snyder A.Z., Powers W.J., Gusnard D.A., Shulman G.L. A default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:676–682. PubMed PMC

Minoshima S., Giordani B., Berent S., Frey K.A., Foster N.L., Kuhl D.E. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol. 1997;42:85–94. PubMed

Johnson K.A., Jones K., Holman B.L., Becker J.A., Spiers P.A., Satlin A., et al. Preclinical prediction of Alzheimer's disease using SPECT. Neurology. 1998;50:1563–1571. PubMed

Matsuda H. Cerebral blood flow and metabolic abnormalities in Alzheimer's disease. Ann Nucl Med. 2001;15:85–92. PubMed

Bradley K.M., O'Sullivan V.T., Soper N.D., Nagy Z., King E.M., Smith A.D., et al. Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease. Brain. 2002;125:1772–1781. PubMed

Greicius M.D., Srivastava G., Reiss A.L., Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004;101:4637–4642. PubMed PMC

De Strooper B., Karran E. The Cellular Phase of Alzheimer's Disease. Cell. 2016;164:603–615. PubMed

Styr B., Slutsky I. Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer's disease. Nat Neurosci. 2018;21:463–473. PubMed PMC

Lam A.D., Deck G., Goldman A., Eskandar E.N., Noebels J., Cole A.J. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease. Nat Med. 2017;23:678–680. PubMed PMC

Vossel K.A., Beagle A.J., Rabinovici G.D., Shu H., Lee S.E., Naasan G., et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013;70:1158–1166. PubMed PMC

Haberman R.P., Branch A., Gallagher M. Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Neurotherapeutics. 2017;14:662–676. PubMed PMC

Mucke L., Selkoe D.J. Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med. 2012;2 PubMed PMC

Mesulam M.M. Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron. 1999;24:521–529. PubMed

Nimmrich V., Ebert U. Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid. Rev Neurosci. 2009;20:1–12. PubMed

Selkoe D.J. Alzheimer's disease is a synaptic failure. Science. 2002;298:789–791. PubMed

Palop J.J., Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009;66:435–440. PubMed PMC

Palop J.J., Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016;17:777–792. PubMed PMC

Kordower J.H., Chu Y., Stebbins G.T., DeKosky S.T., Cochran E.J., Bennett D., et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol. 2001;49:202–213. PubMed

Nygaard H.B., Kaufman A.C., Sekine-Konno T., Huh L.L., Going H., Feldman S.J., et al. Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model. Alzheimers Res Ther. 2015;7:25. PubMed PMC

Verret L., Mann E.O., Hang G.B., Barth A.M., Cobos I., Ho K., et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012;149:708–721. PubMed PMC

Quiroz Y.T., Budson A.E., Celone K., Ruiz A., Newmark R., Castrillon G., et al. Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol. 2010;68:865–875. PubMed PMC

Frere S., Slutsky I. Alzheimer's Disease: From Firing Instability to Homeostasis Network Collapse. Neuron. 2018;97:32–58. PubMed

Kapogiannis D., Mattson M.P. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011;10:187–198. PubMed PMC

Terada T., Obi T., Bunai T., Matsudaira T., Yoshikawa E., Ando I., et al. In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease. Neurology. 2020;94:e1592–e1604. PubMed

Dhapola R., Sarma P., Medhi B., Prakash A., Reddy D.H. Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease. Mol Neurobiol. 2022;59:535–555. PubMed

Kerr J.S., Adriaanse B.A., Greig N.H., Mattson M.P., Cader M.Z., Bohr V.A., et al. Mitophagy and Alzheimer's Disease: Cellular and Molecular Mechanisms. Trends Neurosci. 2017;40:151–166. PubMed PMC

Yin J., VanDongen A.M. Enhanced Neuronal Activity and Asynchronous Calcium Transients Revealed in a 3D Organoid Model of Alzheimer's Disease. ACS Biomater Sci Eng. 2021;7:254–264. PubMed

Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K., et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–872. PubMed

Yu J., Vodyanik M.A., Smuga-Otto K., Antosiewicz-Bourget J., Frane J.L., Tian S., et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–1920. PubMed

Li X.J., Zhang X., Johnson M.A., Wang Z.B., Lavaute T., Zhang S.C. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 2009;136:4055–4063. PubMed PMC

Erceg S., Lainez S., Ronaghi M., Stojkovic P., Perez-Arago M.A., Moreno-Manzano V., et al. Differentiation of human embryonic stem cells to regional specific neural precursors in chemically defined medium conditions. PLoS One. 2008;3:e2122. PubMed PMC

Liu Y., Liu H., Sauvey C., Yao L., Zarnowska E.D., Zhang S.C. Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc. 2013;8:1670–1679. PubMed PMC

Duan L., Bhattacharyya B.J., Belmadani A., Pan L., Miller R.J., Kessler J.A. Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death. Mol Neurodegener. 2014;9:3. PubMed PMC

Chambers S.M., Fasano C.A., Papapetrou E.P., Tomishima M., Sadelain M., Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275–280. PubMed PMC

B. Foveau, A.S. Correia, S.S. Hebert, S. Rainone, O. Potvin, M.J. Kergoat, S. Belleville, S. Duchesne, A.C. LeBlanc, and C.-Q.C.f.t.e.i.o.A.s.d.-Q. the, Stem Cell-Derived Neurons as Cellular Models of Sporadic Alzheimer's Disease. Journal of Alzheimer's disease : JAD 67 (2019) 893-910. PubMed

Ochalek A., Mihalik B., Avci H.X., Chandrasekaran A., Teglasi A., Bock I., et al. Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther. 2017;9:90. PubMed PMC

Jafari Z., Kolb B.E., Mohajerani M.H. Neural oscillations and brain stimulation in Alzheimer's disease. Prog Neurobiol. 2020;194 PubMed

Kim K., Lee C.H., Park C.B. Chemical sensing platforms for detecting trace-level Alzheimer's core biomarkers. Chem Soc Rev. 2020;49:5446–5472. PubMed

Sala Frigerio C., De Strooper B. Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics. Annu Rev Neurosci. 2016;39:57–79. PubMed

Choi S.H., Kim Y.H., Hebisch M., Sliwinski C., Lee S., D'Avanzo C., et al. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014;515:274–278. PubMed PMC

Oberheim N.A., Takano T., Han X., He W., Lin J.H., Wang F., et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276–3287. PubMed PMC

[The role of Italian cardiology in the Italian Group for the Study of Streptokinase in Myocardial Infarct. Distribution, structural and organizational characteristics of coronary intensive care units]. G Ital Cardiol 17 (1987) 14-9. PubMed

Smith A.M., Dragunow M. The human side of microglia. Trends Neurosci. 2014;37:125–135. PubMed

Palop J.J., Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci. 2010;13:812–818. PubMed PMC

Bertram L., Lill C.M., Tanzi R.E. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68:270–281. PubMed

Yagi T., Ito D., Okada Y., Akamatsu W., Nihei Y., Yoshizaki T., et al. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet. 2011;20:4530–4539. PubMed

Armijo E., Gonzalez C., Shahnawaz M., Flores A., Davis B., Soto C. Increased susceptibility to Abeta toxicity in neuronal cultures derived from familial Alzheimer's disease (PSEN1-A246E) induced pluripotent stem cells. Neurosci Lett. 2017;639:74–81. PubMed

Moore S., Evans L.D., Andersson T., Portelius E., Smith J., Dias T.B., et al. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015;11:689–696. PubMed PMC

Yang J., Zhao H., Ma Y., Shi G., Song J., Tang Y., et al. Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget. 2017;8:7900–7913. PubMed PMC

Sproul A.A., Jacob S., Pre D., Kim S.H., Nestor M.W., Navarro-Sobrino M., et al. Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors. PLoS One. 2014;9:e84547. PubMed PMC

Israel M.A., Yuan S.H., Bardy C., Reyna S.M., Mu Y., Herrera C., et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012;482:216–220. PubMed PMC

Chang C.Y., Ting H.C., Liu C.A., Su H.L., Chiou T.W., Harn H.J., et al. Induced Pluripotent Stem Cells: A Powerful Neurodegenerative Disease Modeling Tool for Mechanism Study and Drug Discovery. Cell Transplant. 2018;27:1588–1602. PubMed PMC

Chang K.H., Lee-Chen G.J., Huang C.C., Lin J.L., Chen Y.J., Wei P.C., et al. Modeling Alzheimer's Disease by Induced Pluripotent Stem Cells Carrying APP D678H Mutation. Mol Neurobiol. 2019;56:3972–3983. PubMed PMC

Kondo T., Asai M., Tsukita K., Kutoku Y., Ohsawa Y., Sunada Y., et al. Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell. 2013;12:487–496. PubMed

Muratore C.R., Zhou C., Liao M., Fernandez M.A., Taylor W.M., Lagomarsino V.N., et al. Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability. Stem Cell Rep. 2017;9:1868–1884. PubMed PMC

Wenk G.L. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry. 2003;64(Suppl 9):7–10. PubMed

Liao M.C., Muratore C.R., Gierahn T.M., Sullivan S.E., Srikanth P., De Jager P.L., et al. Single-Cell Detection of Secreted Abeta and sAPPalpha from Human IPSC-Derived Neurons and Astrocytes. J Neurosci. 2016;36:1730–1746. PubMed PMC

Vazin T., Ball K.A., Lu H., Park H., Ataeijannati Y., Head-Gordon T., et al. Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease. Neurobiol Dis. 2014;62:62–72. PubMed PMC

Hamlett E.D., Ledreux A., Potter H., Chial H.J., Patterson D., Espinosa J.M., et al. Exosomal biomarkers in Down syndrome and Alzheimer's disease. Free Radic Biol Med. 2018;114:110–121. PubMed PMC

Dashinimaev E.B., Artyuhov A.S., Bolshakov A.P., Vorotelyak E.A., Vasiliev A.V. Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer's Disease Type Pathology in vitro. Journal of Alzheimer's disease : JAD. 2017;56:835–847. PubMed

Shi Y., Kirwan P., Smith J., MacLean G., Orkin S.H., Livesey F.J. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Sci Transl Med. 2012;4:124ra29. PubMed PMC

Graff-Radford N.R., Crook J.E., Lucas J., Boeve B.F., Knopman D.S., Ivnik R.J., et al. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol. 2007;64:354–362. PubMed

Ovchinnikov D.A., Korn O., Virshup I., Wells C.A., Wolvetang E.J. The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons. Stem Cell Rep. 2018;11:32–42. PubMed PMC

Woodruff G., Young J.E., Martinez F.J., Buen F., Gore A., Kinaga J., et al. The presenilin-1 DeltaE9 mutation results in reduced gamma-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep. 2013;5:974–985. PubMed PMC

P. Martin-Maestro, R. Gargini, A.S. A, E. Garcia, L.C. Anton, S. Noggle, O. Arancio, J. Avila, and V. Garcia-Escudero, Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation. Front Mol Neurosci 10 (2017) 291. PubMed PMC

Wezyk M., Szybinska A., Wojsiat J., Szczerba M., Day K., Ronnholm H., et al. Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. Journal of Alzheimer's disease : JAD. 2018;62:175–202. PubMed

Demars M., Hu Y.S., Gadadhar A., Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J Neurosci Res. 2010;88:2103–2117. PubMed PMC

Arber C., Lovejoy C., Harris L., Willumsen N., Alatza A., Casey J.M., et al. Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell Rep. 2021;34 PubMed PMC

Ghatak S., Dolatabadi N., Gao R., Wu Y., Scott H., Trudler D., et al. NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models. Mol Psychiatry. 2021;26:5751–5765. PubMed PMC

Ghatak S., Dolatabadi N., Trudler D., Zhang X., Wu Y., Mohata M., et al. Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. Elife. 2019;8 PubMed PMC

Zhang H., Watrous A.J., Patel A., Jacobs J. Theta and Alpha Oscillations Are Traveling Waves in the Human Neocortex. Neuron. 2018;98:1269–1281 e4. PubMed PMC

Liu X., Wang S., Zhang X., Wang Z., Tian X., He Y. Abnormal amplitude of low-frequency fluctuations of intrinsic brain activity in Alzheimer's disease. Journal of Alzheimer's disease : JAD. 2014;40:387–397. PubMed

Serrano-Pozo A., Das S., Hyman B.T. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 2021;20:68–80. PubMed PMC

J.C. Lambert, C.A. Ibrahim-Verbaas, D. Harold, A.C. Naj, R. Sims, C. Bellenguez, A.L. DeStafano, J.C. Bis, G.W. Beecham, B. Grenier-Boley, G. Russo, T.A. Thorton-Wells, N. Jones, A.V. Smith, V. Chouraki, C. Thomas, M.A. Ikram, D. Zelenika, B.N. Vardarajan, Y. Kamatani, C.F. Lin, A. Gerrish, H. Schmidt, B. Kunkle, M.L. Dunstan, A. Ruiz, M.T. Bihoreau, S.H. Choi, C. Reitz, F. Pasquier, C. Cruchaga, D. Craig, N. Amin, C. Berr, O.L. Lopez, P.L. De Jager, V. Deramecourt, J.A. Johnston, D. Evans, S. Lovestone, L. Letenneur, F.J. Moron, D.C. Rubinsztein, G. Eiriksdottir, K. Sleegers, A.M. Goate, N. Fievet, M.W. Huentelman, M. Gill, K. Brown, M.I. Kamboh, L. Keller, P. Barberger-Gateau, B. McGuiness, E.B. Larson, R. Green, A.J. Myers, C. Dufouil, S. Todd, D. Wallon, S. Love, E. Rogaeva, J. Gallacher, P. St George-Hyslop, J. Clarimon, A. Lleo, A. Bayer, D.W. Tsuang, L. Yu, M. Tsolaki, P. Bossu, G. Spalletta, P. Proitsi, J. Collinge, S. Sorbi, F. Sanchez-Garcia, N.C. Fox, J. Hardy, M.C. Deniz Naranjo, P. Bosco, R. Clarke, C. Brayne, D. Galimberti, M. Mancuso, F. Matthews, I. European Alzheimer's Disease, Genetic, D. Environmental Risk in Alzheimer's, C. Alzheimer's Disease Genetic, H. Cohorts for, E. Aging Research in Genomic, S. Moebus, P. Mecocci, M. Del Zompo, W. Maier, H. Hampel, A. Pilotto, M. Bullido, F. Panza, P. Caffarra, et al., Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature genetics 45 (2013) 1452-8. PubMed PMC

Lin Y.T., Seo J., Gao F., Feldman H.M., Wen H.L., Penney J., et al. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018;98:1141–1154 e7. PubMed PMC

Wang C., Najm R., Xu Q., Jeong D.E., Walker D., Balestra M.E., et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018;24:647–657. PubMed PMC

Meyer K., Feldman H.M., Lu T., Drake D., Lim E.T., Ling K.H., et al. REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease. Cell Rep. 2019;26:1112–1127 e9. PubMed PMC

Davis N., Mota B.C., Stead L., Palmer E.O.C., Lombardero L., Rodriguez-Puertas R., et al. Pharmacological ablation of astrocytes reduces Abeta degradation and synaptic connectivity in an ex vivo model of Alzheimer's disease. J Neuroinflammation. 2021;18:73. PubMed PMC

Clarke L.E., Barres B.A. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci. 2013;14:311–321. PubMed PMC

Barres B.A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron. 2008;60:430–440. PubMed

Wang H., Eckel R.H. What are lipoproteins doing in the brain? Trends Endocrinol Metab. 2014;25:8–14. PubMed PMC

Nishimura M., Tomimoto H., Suenaga T., Namba Y., Ikeda K., Akiguchi I., et al. Immunocytochemical characterization of glial fibrillary tangles in Alzheimer's disease brain. Am J Pathol. 1995;146:1052–1058. PubMed PMC

Jackson R.J., Meltzer J.C., Nguyen H., Commins C., Bennett R.E., Hudry E., et al. APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain. 2022;145:3582–3593. PubMed PMC

van de Haar H.J., Burgmans S., Jansen J.F., van Osch M.J., van Buchem M.A., Muller M., et al. Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. Radiology. 2017;282:615. PubMed

Nagele R.G., D'Andrea M.R., Lee H., Venkataraman V., Wang H.Y. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971:197–209. PubMed

Vijayan V.K., Geddes J.W., Anderson K.J., Chang-Chui H., Ellis W.G., Cotman C.W. Astrocyte hypertrophy in the Alzheimer's disease hippocampal formation. Exp Neurol. 1991;112:72–78. PubMed

Olabarria M., Noristani H.N., Verkhratsky A., Rodriguez J.J. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia. 2010;58:831–838. PubMed

Habib N., McCabe C., Medina S., Varshavsky M., Kitsberg D., Dvir-Szternfeld R., et al. Disease-associated astrocytes in Alzheimer's disease and aging. Nat Neurosci. 2020;23:701–706. PubMed PMC

Harris M.E., Wang Y., Pedigo N.W., Jr., Hensley K., Butterfield D.A., Carney J.M. Amyloid beta peptide (25–35) inhibits Na+-dependent glutamate uptake in rat hippocampal astrocyte cultures. J Neurochem. 1996;67:277–286. PubMed

Masliah E., Alford M., DeTeresa R., Mallory M., Hansen L. Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease. Ann Neurol. 1996;40:759–766. PubMed

Krencik R., Weick J.P., Liu Y., Zhang Z.J., Zhang S.C. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol. 2011;29:528–534. PubMed PMC

Jones V.C., Atkinson-Dell R., Verkhratsky A., Mohamet L. Aberrant iPSC-derived human astrocytes in Alzheimer's disease. Cell Death Dis. 2017;8:e2696. PubMed PMC

Shaltouki A., Peng J., Liu Q., Rao M.S., Zeng X. Efficient generation of astrocytes from human pluripotent stem cells in defined conditions. Stem Cells. 2013;31:941–952. PubMed

Oksanen M., Petersen A.J., Naumenko N., Puttonen K., Lehtonen S., Gubert Olive M., et al. PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease. Stem Cell Rep. 2017;9:1885–1897. PubMed PMC

Zhao J., Davis M.D., Martens Y.A., Shinohara M., Graff-Radford N.R., Younkin S.G., et al. APOE epsilon4/epsilon4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum Mol Genet. 2017;26:2690–2700. PubMed PMC

Fong L.K., Yang M.M., Dos Santos Chaves R., Reyna S.M., Langness V.F., Woodruff G., et al. Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid-beta clearance in human astrocytes. J Biol Chem. 2018;293:11341–11357. PubMed PMC

Butt A.M., De La Rocha I.C., Rivera A. Oligodendroglial Cells in Alzheimer's Disease. Advances in Experimental Medicine and Biology. 2019;1175:325–333. PubMed

Desai M.K., Mastrangelo M.A., Ryan D.A., Sudol K.L., Narrow W.C., Bowers W.J. Early oligodendrocyte/myelin pathology in Alzheimer's disease mice constitutes a novel therapeutic target. Am J Pathol. 2010;177:1422–1435. PubMed PMC

Ehrlich M., Mozafari S., Glatza M., Starost L., Velychko S., Hallmann A.L., et al. Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors. Proc Natl Acad Sci U S A. 2017;114:E2243–E2252. PubMed PMC

Erceg S., Ronaghi M., Oria M., Rosello M.G., Arago M.A., Lopez M.G., et al. Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells. 2010;28:1541–1549. PubMed PMC

Hu B.Y., Du Z.W., Zhang S.C. Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc. 2009;4:1614–1622. PubMed PMC

Colonna M., Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu Rev Immunol. 2017;35:441–468. PubMed PMC

Hansen D.V., Hanson J.E., Sheng M. Microglia in Alzheimer's disease. J Cell Biol. 2018;217:459–472. PubMed PMC

Guerreiro R., Wojtas A., Bras J., Carrasquillo M., Rogaeva E., Majounie E., et al. Alzheimer Genetic Analysis, TREM2 variants in Alzheimer's disease. N Engl J Med. 2013;368:117–127. PubMed PMC

Yeh F.L., Hansen D.V., Sheng M. TREM2, Microglia, and Neurodegenerative Diseases. Trends Mol Med. 2017;23:512–533. PubMed

Yeh F.L., Wang Y., Tom I., Gonzalez L.C., Sheng M. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016;91:328–340. PubMed

Lee C.Y.D., Daggett A., Gu X., Jiang L.L., Langfelder P., Li X., et al. Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models. Neuron. 2018;97:1032–1048 e5. PubMed PMC

Cummings D.M., Benway T.A., Ho H., Tedoldi A., Fernandes Freitas M.M., Shahab L., et al. Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood-Brain Barrier Failure. Cereb Cortex. 2017;27:3437–3448. PubMed

Paolicelli R.C., Jawaid A., Henstridge C.M., Valeri A., Merlini M., Robinson J.L., et al. TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron. 2017;95:297–308 e6. PubMed PMC

Reichwald J., Danner S., Wiederhold K.H., Staufenbiel M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation. 2009;6:35. PubMed PMC

Yoshiyama Y., Higuchi M., Zhang B., Huang S.M., Iwata N., Saido T.C., et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–351. PubMed

Maphis N., Xu G., Kokiko-Cochran O.N., Jiang S., Cardona A., Ransohoff R.M., et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138:1738–1755. PubMed PMC

Krabbe G., Halle A., Matyash V., Rinnenthal J.L., Eom G.D., Bernhardt U., et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One. 2013;8:e60921. PubMed PMC

Grathwohl S.A., Kalin R.E., Bolmont T., Prokop S., Winkelmann G., Kaeser S.A., et al. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. 2009;12:1361–1363. PubMed PMC

Keren-Shaul H., Spinrad A., Weiner A., Matcovitch-Natan O., Dvir-Szternfeld R., Ulland T.K., et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017;169:1276–1290 e17. PubMed

Xu M., Zhang L., Liu G., Jiang N., Zhou W., Zhang Y. Pathological Changes in Alzheimer's Disease Analyzed Using Induced Pluripotent Stem Cell-Derived Human Microglia-Like Cells. Journal of Alzheimer's disease : JAD. 2019;67:357–368. PubMed

Malm T.M., Jay T.R., Landreth G.E. The evolving biology of microglia in Alzheimer's disease. Neurotherapeutics. 2015;12:81–93. PubMed PMC

Lancaster M.A., Renner M., Martin C.A., Wenzel D., Bicknell L.S., Hurles M.E., et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–379. PubMed PMC

Camp J.G., Badsha F., Florio M., Kanton S., Gerber T., Wilsch-Brauninger M., et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A. 2015;112:15672–15677. PubMed PMC

Garcez P.P., Loiola E.C., Madeiro da Costa R., Higa L.M., Trindade P., Delvecchio R., et al. Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016;352:816–818. PubMed

Velasco S., Kedaigle A.J., Simmons S.K., Nash A., Rocha M., Quadrato G., et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019;570:523–527. PubMed PMC

Quadrato G., Nguyen T., Macosko E.Z., Sherwood J.L., Min Yang S., Berger D.R., et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature. 2017;545:48–53. PubMed PMC

Raja W.K., Mungenast A.E., Lin Y.T., Ko T., Abdurrob F., Seo J., et al. Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One. 2016;11:e0161969. PubMed PMC

Gonzalez C., Armijo E., Bravo-Alegria J., Becerra-Calixto A., Mays C.E., Soto C. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry. 2018;23:2363–2374. PubMed PMC

Zhao J., Fu Y., Yamazaki Y., Ren Y., Davis M.D., Liu C.C., et al. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids. Nat Commun. 2020;11:5540. PubMed PMC

Leng F., Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17:157–172. PubMed

Park J., Wetzel I., Marriott I., Dreau D., D'Avanzo C., Kim D.Y., et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci. 2018;21:941–951. PubMed PMC

Bhaduri A., Andrews M.G., Mancia Leon W., Jung D., Shin D., Allen D., et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature. 2020;578:142–148. PubMed PMC

Sivitilli A.A., Gosio J.T., Ghoshal B., Evstratova A., Trcka D., Ghiasi P., et al. Robust production of uniform human cerebral organoids from pluripotent stem cells. Life Sci Alliance. 2020;3 PubMed PMC

Pomeshchik Y., Klementieva O., Gil J., Martinsson I., Hansen M.G., de Vries T., et al. Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies. Stem Cell Rep. 2020;15:256–273. PubMed PMC

Yoshihara M., Hayashizaki Y., Murakawa Y. Genomic Instability of iPSCs: Challenges Towards Their Clinical Applications. Stem Cell Rev Rep. 2017;13:7–16. PubMed PMC

Miller J., Studer L. Aging in iPS cells. Aging. 2014;6:246–247. PubMed PMC

Sanchez-Danes A., Richaud-Patin Y., Carballo-Carbajal I., Jimenez-Delgado S., Caig C., Mora S., et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med. 2012;4:380–395. PubMed PMC

Qian X., Nguyen H.N., Song M.M., Hadiono C., Ogden S.C., Hammack C., et al. Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell. 2016;165:1238–1254. PubMed PMC

Vierbuchen T., Ostermeier A., Pang Z.P., Kokubu Y., Sudhof T.C., Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463:1035–1041. PubMed PMC

Xu G., Wu F., Gu X., Zhang J., You K., Chen Y., et al. Direct Conversion of Human Urine Cells to Neurons by Small Molecules. Sci Rep. 2019;9:16707. PubMed PMC

Tanabe K., Ang C.E., Chanda S., Olmos V.H., Haag D., Levinson D.F., et al. Transdifferentiation of human adult peripheral blood T cells into neurons. Proc Natl Acad Sci U S A. 2018;115:6470–6475. PubMed PMC

Mertens J., Paquola A.C.M., Ku M., Hatch E., Bohnke L., Ladjevardi S., et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell. 2015;17:705–718. PubMed PMC

Mertens J., Reid D., Lau S., Kim Y., Gage F.H. Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases. Annu Rev Genet. 2018;52:271–293. PubMed PMC

Ladewig J., Mertens J., Kesavan J., Doerr J., Poppe D., Glaue F., et al. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods. 2012;9:575–578. PubMed

Liu M.L., Zang T., Zou Y., Chang J.C., Gibson J.R., Huber K.M., et al. Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun. 2013;4:2183. PubMed PMC

Hu W., Qiu B., Guan W., Wang Q., Wang M., Li W., et al. Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Cell Stem Cell. 2015;17:204–212. PubMed

Qian X., Song H., Ming G.L. Brain organoids: advances, applications and challenges. Development. 2019;146 PubMed PMC

Qian X., Jacob F., Song M.M., Nguyen H.N., Song H., Ming G.L. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc. 2018;13:565–580. PubMed PMC