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APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.
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Apolipoproteína E4 , Encéfalo , Colesterol , Fibras Nervosas Mielinizadas , Oligodendroglia , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Autopsia , Células-Tronco Pluripotentes Induzidas , Neurônios/metabolismo , Neurônios/patologia , Heterozigoto , Transporte Biológico , Homeostase , Análise de Célula Única , Memória , Envelhecimento/genética , Perfilação da Expressão Gênica , Bainha de Mielina/metabolismo , Bainha de Mielina/patologiaRESUMO
Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes were also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD.
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Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aß accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δp35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.
Assuntos
Quinase 5 Dependente de Ciclina/genética , Demência Frontotemporal/genética , Fosfotransferases/genética , Células-Tronco Pluripotentes , Tauopatias/genética , Animais , Região CA3 Hipocampal/patologia , Região CA3 Hipocampal/fisiopatologia , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Demência Frontotemporal/prevenção & controle , Humanos , Potenciação de Longa Duração/genética , Camundongos , Camundongos Transgênicos , Fibras Musgosas Hipocampais/patologia , Fosforilação , Fosfotransferases/antagonistas & inibidores , Transplante de Células-Tronco , Sinapses/patologia , Sinaptofisina/genética , Tauopatias/prevenção & controleRESUMO
Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) and characterized by a wide range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide "chromosomal introversion," disruption of lamina-associated domains, and global chromatin accessibility changes in response to T21, consistent with the transcriptional and nuclear architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular, and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS.
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Síndrome de Down , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Perfilação da Expressão Gênica , Humanos , Transcriptoma/genéticaRESUMO
Cone-rod dystrophy (CORD) is a type of progressive hereditary retinal dystrophies that causes cone predominant photoreceptor degeneration characterized by wide genotypic and phenotypic heterogeneity. Macular cyst (MC) occurs very infrequently in the pediatric age group and has rarely been described in CORD. We report a case of young-onset CORD that was affected by an isolated ABCA4 mutation complicated by the development of MC. Through serial spectral-domain ocular coherence tomography MC has been observed to persist for 24 months before its resolution, followed by retinal thinning and macular atrophy with corresponding visual acuity decline. The formation of MC and visual acuity appeared to be directly correlated in ABCA4-related CORD and its manifestation is invaluable in predicting eventual visual loss. We further speculate that dysfunctional outer blood-retinal barrier may play a role in the pathophysiology of MC development in CORD.
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PURPOSE: To report the germicidal range ultraviolet (UV) irradiation-induced phototoxicity because of unprotected exposure to the UV lamps for presumed household disinfection of SARS-CoV-2 in a domestic setting. METHODS: We report on a family of 3 adults who experienced photophobia, intense eye pain, epiphora, blurred vision, and a burning sensation over the face and neck area after a short period of unprotected exposure to the UV germicidal lamps. RESULTS: An initial examination revealed erythema and tenderness over the face and neck area, reduced visual acuity of 6/12, and conjunctival injections bilaterally in all 3 patients. Further assessment at the ophthalmology department 3 days later revealed gradual improvement of visual acuity to 6/6 bilaterally. Slit-lamp examinations revealed few punctate epithelial erosions. Fundal examinations were normal without evidence of solar retinopathy. The patients were diagnosed with germicidal range UV irradiation-induced photokeratitis and epidermal phototoxicity. Lubricants and emollients were prescribed for symptom relief, and the patients were warned against using a UV germicidal lamp for disinfection purposes without appropriate protection. CONCLUSIONS: Although SARS-CoV-2 is structurally akin to SARS-CoV-1 and MERS-CoV, and previous studies demonstrated high levels of inactivation of beta-coronavirus with germicidal-range UV, evidence for its efficacy to inactivate SARS-CoV-2 is lacking. This case report serves to emphasize the potential consequences of phototoxicity from the improper use of UV germicidal lamps for household disinfection and to highlight the fact that UV germicidal lamps currently have no established role in household disinfection of SARS-CoV-2.
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COVID-19/prevenção & controle , Dermatite Fototóxica/etiologia , Desinfecção/instrumentação , Fotofobia/etiologia , Lesões por Radiação/etiologia , SARS-CoV-2 , Raios Ultravioleta/efeitos adversos , Adolescente , COVID-19/diagnóstico , Dermatite Fototóxica/diagnóstico , Dor Ocular/diagnóstico , Dor Ocular/etiologia , Feminino , Humanos , Controle de Infecções/instrumentação , Fotofobia/diagnóstico , Lesões por Radiação/diagnóstico , Inativação de Vírus/efeitos da radiaçãoRESUMO
While gene expression profiling has traditionally been the method of choice for large-scale perturbational profiling studies, proteomics has emerged as an effective tool in this context for directly monitoring cellular responses to perturbations. We previously reported a pilot library containing 3400 profiles of multiple perturbations across diverse cellular backgrounds in the reduced-representation phosphoproteome (P100) and chromatin space (Global Chromatin Profiling, GCP). Here, we expand our original dataset to include profiles from a new set of cardiotoxic compounds and from astrocytes, an additional neural cell model, totaling 5300 proteomic signatures. We describe filtering criteria and quality control metrics used to assess and validate the technical quality and reproducibility of our data. To demonstrate the power of the library, we present two case studies where data is queried using the concept of "connectivity" to obtain biological insight. All data presented in this study have been deposited to the ProteomeXchange Consortium with identifiers PXD017458 (P100) and PXD017459 (GCP) and can be queried at https://clue.io/proteomics .
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Antineoplásicos/toxicidade , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cardiotoxinas/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Proteômica , Linhagem Celular Tumoral , Humanos , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , ProteomaRESUMO
Hybrid peripheral nerve sheath tumors (HPNST) are recently classified tumors from the World Health Organization Classification of soft tissue tumors that display combined features of more than one peripheral nerve sheath tumor. Acknowledgment is important because of its association with the development of neurofibromatosis type 1, type 2, and schwannomatosis. Orbital involvement is rare and only six cases of HPNST have been documented on literature. This article serves to review the pathophysiology, clinical manifestation, diagnosis, treatment, and prognosis of this infrequent but important orbital tumor.
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BACKGROUND: Microphthalmia, anophthalmia, coloboma (MAC) complex is a spectrum of ocular abnormalities that occur in isolation or as part of a syndrome. Genetic abnormalities have been shown to account for 80% of cases in bilateral anophthalmia or severe microphthalmia, where 25-30% were attributed to chromosomal defects in this subset of MAC patients. To date, chromosome 9 short arm (9p) abnormalities have not been shown to associate with development of MAC. PURPOSE: To report a case of MAC spectrum disorder that is related to 9p deletion and duplication. MATERIALS AND METHODS: A child who exhibited signs of MAC was evaluated retrospectively. Genetic analysis with comparative genomic hybridization (CGH) and a family pedigree was obtained from the proband. RESULTS: A 3-year-old girl with a history of an atrial septal defect, a horseshoe kidney and global developmental delay was presented. Ophthalmic examination revealed bilateral iris coloboma, bilateral choroidal-retinal coloboma, and left-sided microphthalmia. Subsequent oligonucleotide-based array CGH revealed two different sites of duplication and deletion on 9p (9p24.3 (209020_1143516)x1, 9p24.3p24.1 (1158662_6395264)x3). CONCLUSION: We present the first case of MAC spectrum disorder that is related to 9p deletion and duplication. The link between the associated genetic abnormality and the phenotypic features is yet to be established. Duplication of JAK2 gene, which is within the same region of abnormalities, may have potentiated the development of MAC spectrum disease.
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Anoftalmia/patologia , Deleção Cromossômica , Coloboma/patologia , Duplicação Gênica , Janus Quinase 2/genética , Microftalmia/patologia , Anoftalmia/complicações , Anoftalmia/genética , Pré-Escolar , Cromossomos Humanos Par 9 , Coloboma/complicações , Coloboma/genética , Feminino , Humanos , Masculino , Microftalmia/complicações , Microftalmia/genética , LinhagemRESUMO
PURPOSE: Primary orbital schwannoma (POS) is a slow growing, benign encapsulated peripheral nerve sheath tumor that occurs infrequently within the orbit. Recurrence of POS is extremely rare. Previous speculations for reasons of recurrence include incomplete excision and tumor seeding. OBSERVATIONS: We present the fifth case reported in the literature to date of POS that had 2 episodes of recurrences within 8 years after diagnosis, in which rapid and insidious relapses were observed after initial surgical resection. This is also the first reported recurrent POS in which topical Mitomycin-C (MMC) has been employed during surgical excision with an aim to prevent further recurrences. CONCLUSIONS: AND IMPORTANCE: Whilst complete surgical excision remained the standard for management for most POS, when there are multiple recurrences and in cases where total excision is not possible, addition of topical MMC may be an option that may bring about tumour regression as demonstrated in our case.
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In Alzheimer's disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood-brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin-nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin-NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin-NFAT signaling as a therapeutic target in CAA and Alzheimer's disease.
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Apolipoproteína E4/genética , Barreira Hematoencefálica/metabolismo , Calcineurina/metabolismo , Angiopatia Amiloide Cerebral/genética , Fatores de Transcrição NFATC/genética , Pericitos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Barreira Hematoencefálica/citologia , Humanos , Técnicas In Vitro , Células-Tronco Pluripotentes Induzidas , Fatores de Transcrição NFATC/metabolismo , Permeabilidade , RNA-Seq , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
PURPOSE: Tsukamurella is an important and emerging organism that causes opportunistic human infection. We present the largest case series of Tsukamurella species-associated ophthalmic infections, with an emphasis on clinical spectrum, risk factors, treatment, and outcome. METHODS: A case series of culture-positive Tsukamurella species in ocular microbiological specimens was identified retrospectively from 2005 to 2018. Tsukamurella species were identified by phenotypic, molecular, and genotypic methods. Diagnoses were clinical and were supplemented by microbiological findings. Treatment including antibiotic type, number of antibiotics, treatment duration, and clinical outcome was documented. RESULTS: Eleven cases of culture-positive Tsukamurella ocular infection were identified. Of these 54.5% (6/11) of cases resulted in conjunctivitis, 18% (2/11) of cases resulted in keratitis, and 9% (1/11) of cases resulted in blepharitis. One case of canaliculitis and 1 case of postenucleation ocular implant-related infection were reported, which were both novel findings. The presence of ocular implant and preexisting ocular surface diseases such as exposure keratopathy and ectropion were thought to be predisposing factors. We have demonstrated that treatment of Tsukamurella ocular conjunctivitis, keratitis, and blepharitis was effective using a combination therapy of 2 antibiotics (fluoroquinolone, fusidic acid, or chloramphenicol). Canaliculitis and ocular implant infection required further addition of oral antibiotics (macrolide or doxycycline), canaliculotomy, and removal of the infected implant for satisfactory management. CONCLUSIONS: Tsukamurella tyrosinosolvens and Tsukamurella pulmonis were found to be the predominant species that caused ocular infection. Ocular manifestation of Tsukamurella has a wider spectrum than that previously reported. A high-level of suspicion and a low threshold for microbiological sampling in cases with prolonged ocular surface infection are recommended to diagnose Tsukamurella infections.
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Infecções por Actinomycetales/microbiologia , Actinomycetales/isolamento & purificação , Enucleação Ocular/efeitos adversos , Infecções Oculares Bacterianas/microbiologia , Implantes Orbitários/efeitos adversos , Infecções Relacionadas à Prótese/microbiologia , Actinomycetales/genética , Infecções por Actinomycetales/diagnóstico , Infecções por Actinomycetales/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , DNA Bacteriano/análise , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Implantes Orbitários/microbiologia , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/tratamento farmacológico , Estudos RetrospectivosRESUMO
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aß42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aß uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aß phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. VIDEO ABSTRACT.
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Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Sistemas CRISPR-Cas , Diferenciação Celular , Humanos , Metabolismo dos Lipídeos , Microglia/imunologia , Microglia/metabolismo , Organoides/metabolismo , Fosfoproteínas/metabolismo , Transmissão Sináptica , TranscriptomaRESUMO
Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the "connectivity" framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics.
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Bases de Dados Factuais , Fosfoproteínas/efeitos dos fármacos , Algoritmos , Linhagem Celular , Cromatografia Líquida , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Código das Histonas , Humanos , Espectrometria de Massas , Fenômenos Farmacológicos e Toxicológicos , Fosfoproteínas/metabolismo , Proteômica , Transdução de Sinais , SoftwareRESUMO
Fluorescent live imaging of cells and embryos at subcellular resolution poses significant challenges for biologists due to morbidity and mortality ensuing from phototoxicity. Here we report the use of a spinning-disk confocal microscope to image mouse and bovine preimplantation embryos without impairing their developmental potential. We also present data indicating that this imaging technique does not affect the functionality of subcellular components as assessed by reactive oxygen species (ROS) production, caspase activity, and DNA integrity. Spinning-disk confocal microscopy was also useful in determining cell number and allocation in transgenic bovine blastocysts. We conclude that this imaging method is suitable for monitoring preimplantation embryos.
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Blastocisto/fisiologia , Blastocisto/ultraestrutura , Desenvolvimento Embrionário , Microscopia Confocal/métodos , Animais , Bovinos , Núcleo Celular/ultraestrutura , Feminino , Camundongos , Espécies Reativas de OxigênioRESUMO
Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.
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Fatores de Transcrição Forkhead/metabolismo , Histona Desacetilases/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Comportamento Social , Animais , Humanos , Camundongos Transgênicos , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Fenótipo , Síndrome de Rett/genéticaRESUMO
The dismal success rate of clinical trials for Alzheimer's disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD) patients harboring amyloid precursor protein (APP) duplication or presenilin1 (PSEN1) mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with ß- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD.