Human iPSC-derived Neurons Research Articles

From the Cover: Manganese and Rotenone-Induced Oxidative Stress Signatures Differ in iPSC-Derived Human Dopamine Neurons.

Parkinson's disease (PD) is the result of complex interactions between genetic and environmental factors. Two chemically distinct environmental stressors relevant to PD are the metal manganese and the pesticide rotenone. Both are thought to exert neurotoxicity at least in part via oxidative stress resulting from impaired mitochondrial activity. Identifying shared mechanism of action may reveal clues towards an understanding of the mechanisms underlying PD pathogenesis. Here we compare the effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons by assessing several different oxidative stress endpoints. Manganese, but not rotenone caused a concentration and time-dependent increase in intracellular reactive oxygen/nitrogen species measured by quantifying the fluorescence of oxidized chloromethyl 2',7'-dichlorodihydrofluorescein diacetate (DCF) assay. In contrast, rotenone but not manganese caused an increase in cellular isoprostane levels, an indicator of lipid peroxidation. Manganese and rotenone both caused an initial decrease in cellular reduced glutathione; however, glutathione levels remained low in neurons treated with rotenone for 24 h but recovered in manganese-exposed cells. Neurite length, a sensitive indicator of overall neuronal health was adversely affected by rotenone, but not manganese. Thus, our observations suggest that the cellular oxidative stress evoked by these 2 agents is distinct yielding unique oxidative stress signatures across outcome measures. The protective effect of rasagiline, a compound used in the clinic for PD, had negligible impact on any of oxidative stress outcome measures except a subtle significant decrease in manganese-dependent production of reactive oxygen/nitrogen species detected by the DCF assay.

Astrocyte-enriched feeder layers from cryopreserved cells support differentiation of spontaneously active networks of human iPSC-derived neurons

BackgroundHuman induced pluripotent stem cell (hiPSC)-derived neuronal cultures are a useful tool for studying the mechanisms of neurological disorders and developing novel therapeutics. While plating hiPSC-derived neuronal progenitors onto glial feeder layers prepared from rodent cortex has been reported to promote functional differentiation of neuronal networks, this has not been examined in detail. New methodHere we describe a method of using cryopreserved cells from primary cultures for generation of mouse astrocyte-enriched, neuron-free feeder layers that grow from 10% to 100% confluence in 1 week. ResultsElectrophysiological analysis demonstrated that compared to biochemical substrates alone, astrocyte-enriched feeder layers support more rapid differentiation of hiPSC-derived progenitors into excitable neurons that form spontaneously active networks in culture. There was a positive correlation between the degree of astroglial confluence at the time of progenitor plating and the average frequency of postsynaptic currents 3 weeks after plating. One disadvantage to plating on 100% confluent feeder layers was a high incidence of the astroglial layer with the overlying neurons detaching from the coverslips during transfer to the recording chamber. Comparison with existing method(s)Prevailing methods using primary glial feeder layers can result in possible contamination with rodent neurons and an unpredictable rate of growth. We provide a reliable method of generating mouse astroglial feeder layers from cryopreserved primary cultures to support differentiation of hiPSC-derived neurons. ConclusionsThe ability to make astrocyte-enriched feeder layers of defined confluence from cryopreserved primary cultures will facilitate the use of human stem cell derived neuronal cultures for disease modeling.

Lysophosphatidic acid signaling regulates the KLF9-PPARγ axis in human induced pluripotent stem cell-derived neurons

Lysophosphatidic acid (LPA) is a lipid signaling molecule that plays several significant roles in the nervous system during development and injury. In this study, we differentiated human induced pluripotent stem cells (iPSCs) into neurons as an in vitro model to examine the specific effects of LPA. We demonstrated that LPA activates peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated nuclear receptor, as well as its cognate receptor LPA1 on human iPSC-derived neurons to enhance proliferation and neurite outgrowth. Furthermore, we found that the gene expression of Kruppel-like factor 9 (KLF9), a member of the large KLF transcription factor family, was induced by LPA treatment. Knockdown of KLF9 decreased proliferation and neurite outgrowth in vehicle- and LPA-treated IPSC-derived neurons compared to cells expressing KLF9. In conclusion, LPA plays dual roles as a ligand mediator through the activation of cell surface G-coupled protein receptors and as an intracellular second messenger through the activation of PPARγ. We discuss the contribution of the LPA1-PPARγ-KLF9 axis to neurite outgrowth and proliferation in human iPSC-derived neurons.

NOVEL METHOD FOR OLIGOMERIC Aβ DETECTION REVEALS INTRACELLULAR ACCUMULATION OF Aβ UPON LOW-DOSE TREATMENT WITH A GAMMA-SECRETASE INHIBITOR

As the focus for Aβ-induced Alzheimer's disease (AD) pathology has shifted towards the oligomeric forms, there is a need for specific and sensitive detection of oligomeric Aβ (oAβ). Additionally, clinical trials using γ-secretase inhibitors have been halted due to lack of clinical efficacy and/or side effects. Recent in vitro studies suggest that low doses of γ-secretase inhibitors (GSI) may increase Aβ production. We hypothesised that low-dose treatment with the GSI DAPT could cause intracellular accumulation of oAβ and developed a novel method to monitor this process. A novel method for specific detection of oligomeric Aβ (oAβ) was developed using Duolink techology, where an Aβ N-terminal specific antibody was conjugated to Duolink PLUS and MINUS probes, respectively. The method was optimized using oAβ-fed SH-SY5Y cells and was thereafter used to study intracellular accumulation of oAβ in iPSC-derived human cortical neurons exposed to low doses of DAPT. Secreted levels of Aβ were also investigated upon DAPT treatment using mass spectrometry and immunocytochemical methods. Duolink probe-labelled 82E1 antibody successfully detected oAβ in cultured SH-SY5Y cells. The method was sensitive (lower limit of detection <125 nM) (Figure 1) and specific for the oligomeric form (no cross-reactivity with monomeric N-terminal Aβ fragments). Furthermore, low-dose treatment (2 and 20 nM) with DAPT increased the secretion of several Aβ peptides from iPSC derived human cortical neurons. This was accompanied by intracellular accumulation oAβ (Figure 2).

ACUTE, TRANSIENT INCREASE IN SECRETION OF NEURODEGENERATION BIOMARKERS AFTER IRRADIATION OF HUMAN CORTICAL NEURONS

Radiotherapy is a commonly used therapy for brain tumor control or prevention, but many patients display persistent and deteriorating cognitive function following treatment. Children receiving cranial radiation therapy are especially affected and currently little is known about the underlying mechanisms. The chronic symptoms often become apparent after approximately one year, but could nonetheless be a result of acute cell damage upon irradiation. More understanding of the mechanisms behind radiation-induced acute neuronal damage is needed in order to predict and prevent severe side effects after radiotherapy. We have previously reported a prolonged but transient increase in cerebrospinal fluid levels of the neuronal proteins tau and neurofilament light (NFL) from patients undergoing prophylactic cranial radiotherapy, suggesting a potential for these proteins as biomarkers also for the brain damage observed after irradiation. Here, we use a human cortical cell model to investigate the neuronal release of these proteins in response to ionizing radiation in more detail. Human iPSC-derived cortical neurons were irradiated with a single dose of 0.5-, 1.5- or 4.5-Gy ionizing radiation, respectively, at two time points during differentiation and followed during a four-week period post-irradiation. Cells and media were collected at different time points after irradiation and compared to non-irradiated control. Secreted tau and NFL were measured in the media using electrochemiluminescence assays. Gene expression was monitored with qPCR. Both tau and NFL secretion to the cell media increased dose-dependently during the first four days following irradiation. The secretion peaked after four days and returned to basal or slightly elevated levels within one-two weeks. Despite this, signs of astrocyte activation and altered cell division patterns were still observed one month after irradiation. Effects were more accentuated in cells irradiated at an earlier differentiation stage. Ionizing irradiation of cortical neuronal cultures induced a transient increase in tau and NFL secretion. The observed effects were more accentuated in less differentiated neurons, suggesting that developing neurons are especially sensitive to radiation-induced injury. These results correlate well with the clinical situation, showing the potential for the cell model in further investigation of neuronal responses to radiation-induced cell damage.

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab-paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell® Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.

Human Induced Pluripotent Stem Cell-Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury.

Human motor neurons may be reliably derived from induced pluripotent stem cells (iPSCs). In vivo transplant studies of human iPSCs and their cellular derivatives are essential to gauging their clinical utility. To determine whether human iPSC-derived motor neurons can engraft in an immunodeficient mouse model of sciatic nerve injury. This nonblinded interventional study with negative controls was performed at a biomedical research institute using an immunodeficient, transgenic mouse model. Induced pluripotent stem cell-derived motor neurons were cultured and differentiated. Cells were transplanted into 32 immunodeficient mice with sciatic nerve injury aged 6 to 15 weeks. Tissue analysis was performed at predetermined points after the mice were killed humanely. Animal experiments were performed from February 24, 2015, to May 2, 2016, and data were analyzed from April 7, 2015, to May 27, 2016. Human iPSCs were used to derive motor neurons in vitro before transplant. Evidence of engraftment based on immunohistochemical analysis (primary outcome measure); evidence of neurite outgrowth and neuromuscular junction formation (secondary outcome measure); therapeutic effect based on wet muscle mass preservation and/or electrophysiological evidence of nerve and muscle function (exploratory end point). In 13 of the 32 mice undergoing the experiment, human iPSC-derived motor neurons successfully engrafted and extended neurites to target denervated muscle. Human iPSC-derived motor neurons reduced denervation-induced muscular atrophy (mean [SD] muscle mass preservation, 54.2% [4.0%]) compared with negative controls (mean [SD] muscle mass preservation, 33.4% [2.3%]) (P = .04). No electrophysiological evidence of muscle recovery was found. Human iPSC-derived motor neurons may have future use in the treatment of peripheral motor nerve injury, including facial paralysis. NA.

Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons.

SummaryNeurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+ and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.

InVitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling.

SummaryThe blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.

Abstract WP113: Induced Pluripotent Stem Cells Derived Neurons Ideally Serve as a Human Stroke Model of Neuronal Damage and Neuroprotective Intervention

Background: Basic science research on stroke is lagging. Results from both animal and animal-derived neural cell models are, more often than not, less valid for human stroke. To address this lack of models for human stroke mechanisms, we developed induced pluripotent stem cell (iPSC)-derived human neurons and subjected them to excitotoxicity and oxygen-glucose deprivation (OGD) conditions. These conditions produced a disturbed nitric oxide (NO) metabolome similar to human stroke. A therapeutic intervention, the NO-based neuroprotective agent S-nitrosoglutathione (GSNO), was investigated for neuroprotection against excitotoxicity as well as OGD-induced neuronal nitric oxide synthase (nNOS) activation and the deleterious nNOS/peroxynitrite/calpain neurodegenerative system. Methods: The iPSC were generated using skin fibroblasts from normal adult human subjects. Neural precursor cells (NPC) were prepared using embryonic body and NPC were differentiated into neurons. Results: The differentiated iPSC neurons were positive for NeuN and β-tubulin (neuronal markers), and they responded to glutamate/NMDA-induced Ca 2+ influx. The majority of iPSC neurons (~90%) were nNOS-positive, supporting them as a suitable model for NO metabolome studies. To examine this model’s nNOS/peroxynitrite/calpain system under stroke conditions, nNOS activation (pnNOS)-dependent toxicity in the iPSC-derived neurons was observed. High expression levels were found for pnNOS Ser 1412 , 3-NT, and p25 fragment in glutamate/NMDA- and OGD-treated cells. GSNO treatment reversibly blocked glutamate/NMDA- and OGD-induced pnNOS and 3-NT expression levels. Calpain activity was also blocked. Conclusions: This study of iPSC-derived human neurons is the first of its kind to investigate excitotoxicity or OGD-mediated neurodegeneration mechanisms and therapeutic interventions under stroke conditions. The data provide evidence that the deleterious nNOS/peroxynitrite/calpain system in iPSC neurons is similar to human stroke and that GSNO treatment down regulates this deleterious system. These observations support that iPSC human neurons are a suitable model for studies on stroke-associated neurodegenerative mechanisms as well as therapeutic interventions.

Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease.

While induced pluripotent stem cell (iPSC) technologies enable the study of inaccessible patient cell types, cellular heterogeneity can confound the comparison of gene expression profiles between iPSC-derived cell lines. Here, we purified iPSC-derived human dopaminergic neurons (DaNs) using the intracellular marker, tyrosine hydroxylase. Once purified, the transcriptomic profiles of iPSC-derived DaNs appear remarkably similar to profiles obtained from mature post-mortem DaNs. Comparison of the profiles of purified iPSC-derived DaNs derived from Parkinson’s disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant functional convergence amongst differentially-expressed (DE) genes. The PD LRRK2-G2019S associated profile was positively matched with expression changes induced by the Parkinsonian neurotoxin rotenone and opposed by those induced by clioquinol, a compound with demonstrated therapeutic efficacy in multiple PD models. No functional convergence amongst DE genes was observed following a similar comparison using non-purified iPSC-derived DaN-containing populations, with cellular heterogeneity appearing a greater confound than genotypic background.

Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons.

The role of dopamine D2 and D3 receptors(D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels. In the present study, hiPSCs generated from human dermal fibroblasts were used to produce midbrain DA (mDA) neurons, expressing the proper set of genes and proteins typical of authentic, terminally differentiated DA neurons. In this model, the expression and the functional properties of the human D2R/D3R were investigated with a combination of biochemical and functional techniques. We observed that in hiPSC-derived mDA neurons, the activation of D2R/D3R promotes the proliferation of neuronal progenitor cells. In addition, we found that D2R/D3R activation inhibits nicotine-stimulated DA release and exerts neurotrophic effects on mDA neurons that likely occur via the activation of PI3K-dependent mechanisms. Furthermore, D2R/D3R stimulation counteracts both the aggregation of alpha-synuclein induced by glucose deprivation and the associated neuronal damage affecting both the soma and the dendrites of mDA neurons. Taken together, these data point to the D2R/D3R-related signaling events as a biochemical pathway crucial for supporting both neuronal development and survival and protection of human DA neurons.

The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states

Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy.

Alzheimer's Disease: Insights from Genetic Mouse Models and Current Advances in Human IPSC-Derived Neurons.

Alzheimer's disease was first described in 1906 and since then tremendous efforts have been made to fully understand the disease pathology and to find a cure for this neurodegenerative disease. The diagnosis of Alzheimer's is still difficult, especially in early stages of the disease. Current treatment of Alzheimer's only ameliorates the symptoms but fails to provide a therapy. Over the last decades, animal models have been proven valuable in elucidating insights of the pathology. In vitro models using patient-derived cells are currently emerging and hold great promise in understanding the disease pathophysiology. Here, we introduce the neurobiology and genetic features of Alzheimer's and describe what we have learned from studies employing mouse models and patient-derived induced pluripotent stem cells.

In vitro pain assay in cultured human iPSC-derived sensory neurons using MEA system

In vitro pain assay in cultured human iPSC-derived sensory neurons using MEA system

Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons

Recent studies have pointed to protein S-nitrosylation as a critical regulator of cellular redox homeostasis. For example, S-nitrosylation of peroxiredoxin-2 (Prx2), a peroxidase widely expressed in mammalian neurons, inhibits both enzymatic activity and protective function against oxidative stress. Here, using in vitro and in vivo approaches, we identify a role and reaction mechanism of the reductase sulfiredoxin (Srxn1) as an enzyme that denitrosylates (thus removing -SNO) from Prx2 in an ATP-dependent manner. Accordingly, by decreasing S-nitrosylated Prx2 (SNO-Prx2), overexpression of Srxn1 protects dopaminergic neural cells and human-induced pluripotent stem cell (hiPSC)-derived neurons from NO-induced hypersensitivity to oxidative stress. The pathophysiological relevance of this observation is suggested by our finding that SNO-Prx2 is dramatically increased in murine and human Parkinson's disease (PD) brains. Our findings therefore suggest that Srxn1 may represent a therapeutic target for neurodegenerative disorders such as PD that involve nitrosative/oxidative stress.

Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology.

Human neural progenitors derived from pluripotent stem cells develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology and psychiatry. By combining patch clamping, morphological and transcriptome analysis on single-human neurons in vitro, we defined a continuum of poor to highly functional electrophysiological states of differentiated neurons. The strong correlations between action potentials, synaptic activity, dendritic complexity and gene expression highlight the importance of methods for isolating functionally comparable neurons for in vitro investigations of brain disorders. Although whole-cell electrophysiology is the gold standard for functional evaluation, it often lacks the scalability required for disease modeling studies. Here, we demonstrate a multimodal machine-learning strategy to identify new molecular features that predict the physiological states of single neurons, independently of the time spent in vitro. As further proof of concept, we selected one of the potential neurophysiological biomarkers identified in this study-GDAP1L1-to isolate highly functional live human neurons in vitro.

Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele.

Genetic variation in nicotinic receptor alpha 5 (CHRNA5) has been associated with increased risk of addiction-associated phenotypes in humans yet little is known the underlying neural basis. Induced pluripotent stem cells (iPSCs) were derived from donors homozygous for either the major (D398) or the minor (N398) allele of the nonsynonymous single nucleotide polymorphism (SNP), rs16969968, in CHRNA5. To understand the impact of these nicotinic receptor variants in humans, we differentiated these iPSCs to dopamine (DA) or glutamatergic neurons and then tested their functional properties and response to nicotine. Results show that N398 variant human DA neurons differentially express genes associated with ligand receptor interaction and synaptic function. While both variants exhibited physiological properties consistent with mature neuronal function, the N398 neuronal population responded more actively with an increased excitatory postsynaptic current response upon the application of nicotine in both DA and glutamatergic neurons. Glutamatergic N398 neurons responded to lower nicotine doses (0.1 μM) with greater frequency and amplitude but they also exhibited rapid desensitization, consistent with previous analyses of N398-associated nicotinic receptor function. This study offers a proof-of-principle for utilizing human neurons to study gene variants contribution to addiction.

Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer’s Disease Mutations

We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggest that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD.

Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders

The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders. Postmortem human tissues are available from many biobanks; nevertheless, collections of neuronal human cells from large patient cohorts representing the human diversity remain scarce. Two tools are gaining popularity for personalized medicine research on neuropsychiatric disorders: human induced pluripotent stem cell-derived neurons and human lymphoblastoid cell lines. This review examines and contrasts the advantages and limitations of each tool for personalized medicine research.