The human brain of many individuals is genetically susceptible to neurodegenerative diseases like Alzheimer’s disease (AD) or poor recovery from traumatic injury and chemotherapy. However, pinpointing the genetic elements that promote this pathogenesis, establishing their underlying cellular and molecular mechanisms, and developing therapeutic strategies remain major challenges. These challenges are reflected in the growing patient population and complete absence of therapeutics for Alzheimer’s disease and related dementias. We need new approaches to understand the uniquely human biology that is fundamental to neurodegeneration and innovative technology that enables the development of effective therapeutic and preventative strategies. To fulfill this need, we engineer 3D models of human brain tissue from stem cells and apply these models to understand and therapeutically target risk factors for Alzheimer’s disease and other forms of cognitive impairment.
Our work specifically aims to (1) establish the cellular and molecular pathways underlying neurodegenerative risk factors, (2) target and modulate these pathways as potential therapeutic strategies, and (3) establish pioneering technology and tools that unravel complex genetic, cellular, and environmental interactions in the human brain. Ultimately, our goal is to facilitate a precision medicine approach to understanding and treating neurodegenerative disease.
Joel Blanchard, PhD
Nash Family Department of Neuroscience
Department of Cell, Developmental & Regenerative Biology
Black Family Stem Cell Institute
Ronald M. Loeb Center for Alzheimer’s Disease
Icahn School of Medicine at Mount Sinai
Blanchard J., Victor M., Tsai L-H, Dissecting the complexities of Alzheimer’s disease with in vitro models of the human brain. Nature Reviews Neurology (2021). Link
Blanchard J., Bula M., Akay, LA., Zhu L., Frank A., Velderrian JD., Victor, M., Bonner, JM., Mathys, H., Lin YT., Kellis, M., Cam, H., Tsai LH. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nature Medicine (2020)Link
Blanchard J., Tsai, LH., Unraveling the paradox of statins with human neurons: New leads in Alzheimer’s disease. Cell Stem Cell (2019). Link
Tsunemoto R.*, Lee S.*, Szűcs A., Chubukov P., Sokolova I., Blanchard J., Eade K., Bruggemann J., Su A., Sanna P., Baldwin K., Binary reprogramming codes for neuronal identity and diversity. Nature (2018). Link
Blanchard J., Xie, J., El-Mecharrafie, N., Lerner, RA., Baldwin K., Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries. Nature Biotechnology (2017). Link
Blanchard J*., Eade K*., Szucs A., Lo Sardo V., Tsunemoto R., Williams D., Sanna P., Baldwin K. Selective conversion of fibroblasts into peripheral sensory neurons. Nature Neuroscience (2015) Link
Tsunemoto R., Eade, K., Blanchard J., Baldwin K. Forward engineering neuronal diversity using direct reprogramming. EMBO J (2015). Link
Wang Y., Davidow L., Arvanites A., Blanchard J., Lam K., Woo J., Coy S., Rubin L.L., McMahon A. Selective Identification of Hedgehog pathway antagonists by direct analysis of Smoothened Ciliary Translocation. ACS Chemical Biology (2012). Link
Wang Y., Davidow L., Arvanites A., Blanchard J., Lam K., Woo J., Ng J., Curran T., Rubin L.L., McMahon, A. Glucocorticoids Compounds Modify Smoothened Localization and Hedgehog Pathway Activity. Chemistry and Biology. (2012). Link
Ichida J. K*., Blanchard J*., Lam K*., Son E. Y*., Chung J. E., Egli D., Loh K. M., Carter A. C., Di Giorgio F. P., Koszka K., Huangfu D., Akutsu H., Liu DR., Rubin LL., Eggan A Small-Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog. Cell Stem Cell (2009). Link
*These authors contributed equally to this work
Louise Louro, PhD
Post Doctoral Fellow
Louise has a background in central nervous system injury, biomarkers and regenerative strategies, including cell therapies and pharmacological approaches. Her current research is focused on developing multi-cellular in vitro models of neurodegenerative diseases. She enjoys cooking Brazilian-Italian food and walking around the city to find nice little wine and food spots.
Lea R'Bibo, PhD
Post Doctoral Fellow
Lea’s research focuses on determining the contribution of major genetic variants associated with Alzheimer’s disease on hallmarks of the pathology. Her research interests revolve around understanding the contribution of genetic factors to neurodegenerative diseases using complex pluripotent stem cell derived models. She obtained her PhD in Neuroscience from the Institute of Neurology at University College London. In her free time, she enjoys discovering new restaurants, sifts through bookstores and interesting exhibitions.
Elena Coccia, PhD
Post Doctoral Fellow
Lily Sarrafha, MS
Doctoral Graduate Student
Gustavo Parfitt, PhD
Post Doctoral Fellow
Doctoral Graduate Student
Tatyana obtained her B.S in Medical Laboratory Science from City Medical College in Odessa, Ukraine. She is supporting an administrative as well as technical side of the research projects in the lab. In her free time , Tatyana enjoys exploring New York City and spending time with family.
Eveline Gutzwiller, MD
Post Doctoral Fellow
Areas of Investigation
Blood-Brain Barrier (BBB)
The BBB feeds the brain with nutrients and oxygen while also protecting it from peripheral pathogens and insults. It is increasingly recognized the BBB also has a prominent role in neurodegenerative disease. Numerous genes associated with risk for neurodegeneratoion are expressed in the cells that constitute the BBB where they likely directly influence disease susceptibility and pathogenesis. For example, APOE is highly expressed In the BBB and the APOE4 variants is known to correlate with increased amyloid deposition on cerebral vasculature. In addition to being a location of amyloid deposition, the BBB also forms a highly selective barrier that prevents more than 98% of all small molecules from entering the brain. By developing an iPSC-based model of the BBB, we aim to understand i) how the BBB contributes to neuorodegeneration susceptibility and pathogenesis and ii) develop a physiologically reliable test to asses drug-brain penetration across diverse genetic populations.
It is emerging that oligodendrocytes (OLs) and myelin degeneration play a central role in neurodegeneration and cognitive aging. In the human brain, the total myelin volume increases until around the fourth or fifth decade of life after which it sharply declines. Therefore, myelin degeneration is thought to be a fundamental mechanism leading to cognitive changes associated with aging. In most neurodegenerative diseases, myelin degeneration is accelerated. For example, the majority of Alzheimer’s disease (AD) patients exhibit deficits in white matter compared to healthy individuals of the same age. Surprisingly, in populations at high risk for developing AD, several imaging studies identified that the loss of white matter begins prior to cognitive decline. Likewise, in rodent AD models, myelin deficits are observed prior to the formation of amyloid plaques and neurofibrillary tau tangles, the classical pathological hallmarks of AD. At the molecular level, many of the genes implicated in the development of sporadic AD could directly influence OL biology and/or myelination. Collectively, this suggests that myelin degeneration may be one of the earliest biomarkers and a key pathological mechanism underlying cognitive decline in AD and aging. Despite these implications the role of OLs and myelin degeneration in AD pathogenesis remain largely unclear. This is likely due to species differences in myelin biology, difficulty in procuring mature OLs, and limited assays for human myelination. Through developing technology to study human myelination in a dish we aim to gain deeper insight into how myelination is altered during neurodegeneration and the effect of genetics and the environment on these processes.
In the human brain, neurons, microglia, and the blood-brain barrier are dynamically interconnected. How these connections are formed during development, maintained in homeostasis, and degenerate with age remain poorly understood. It is also largely unclear how human genetic diversity alters neuro-immune-vascular interactions to influence susceptibility to disease and age-related cognitive impairments. To approach these questions, we have developed an in vitro Neuro-Immune-Vascular tissue.
Multi-cellular integrated brain tissue (miBRAIN)
Numerous preclinical drugs have effectively cured Alzheimer’s disease in mice and other vertebrate models. However, all of these once-promising candidates have ultimately failed to show efficacy in human clinical trials. There are general concerns about the fidelity of rodent models and most of the genetic variants associated with increased risk for Alzheimer’s disease in humans are not conserved between species. Therefore, intermediate models that exhibits AD pathology in human tissues may better predict clinical outcomes. To address this, we are creating a multicellular integrated Brain tissue (miBRAIN) composed of seven disease-relavent cell-types. Future studies will apply this models to 1) pinpoint cellular and molecular mechanisms that promote risk for age-related cognitive impairment 2) screen and stratify drug response and efficacy across diverse genetic backgrounds 3) investigate how adverse life events such as traumatic brain injury or chemotherapy increase susceptibility to age-related neurodegeneration.
2021 Friedman Brain Institute Scholar Award
2019 – ISSCR Merit Award
2019 – ISSCR Travel Award, International Society for Stem Cell Research meeting, Los Angles, CA.
2018 – Postdoctoral Fellowship in Aging Research, Glenn Foundation of Medical Research
2014 – Betty Jean Ogawa Memorial Poster Award, International Society for Stem Cell Research
2014 – ISSCR Travel Award, International Society for Stem Cell Research meeting Vancouver, BC.
2014 – Keystone Scholarship, Keystone symposia on Stem cells and Reprogramming, Olympic Valley, CA.
2011 – Pre-doctoral Fellowship, California Institute of Regenerative Medicine.
2010 – ISSCR Travel Award, International Society for Stem Cell Research meeting San Francisco, CA.
2010 – Biotechnology Master’s Thesis Honorable Mention, Harvard University
2009 – ISSCR Travel Award, International Society for Stem Cell Research meeting, Barcelona Spain.
In the News Archives
Extending the longevity of human brain models for longitudinal analysis
Establishing the molecular and cellular mechanisms and biomarkers of APOE4-mediated susceptibility to tau-related cognitive impairments
Studies have demonstrated that the strongest risk factor for Alzheimer’s disease APOE4 increases the severity of Tau pathology and cognitive impairments, but the mechanisms are unknown. Using our in vitro brain technology, we will dissect the cellular and molecular mechanisms by which APOE genotype modulates Tau phenotypes. This will reveal signaling pathways that we will investigate as therapeutic targets using chemical and genetic approaches.
Implications of Polyamine and Glucosylceramide Transport for Parkinson’s Disease (IMPACT-PD)
This grant seeks to understand the role of ATP13A2 and ATP10B in PD-associated lysosomal dysfunction. Our group will collaborate with other investigators in establishing, validating and characterizing all in vitro cell models. We will lead the efforts to generate midbrain dopaminergic neurons, midbrain patterned astrocytes, co-cultures and phenotyping efforts in hPSC derived differentiated cells.
UG3-NS115064 Construction of an integrated immune-vascular brain- chip as a platform for the study, drug screening, and treatments of Alzheimer’s disease
This grant builds off our iBBB technology by incorporating additional cells types to generate a human multicellular integrated brain tissue (miBrain). Using iPSC lines from which we have matched post-mortem brains we will develop, optimize, and validate this human brain-on-a-chip technology as platform for the study, screening and therapeutic optimization of Alzheimer’s disease.
R01NS114239 Understanding cell-type vulnerability and oxidative stress pathology in Parkinson’s Disease using isogenic human dopaminergic neurons
This grant investigates site-specific vulnerability of dopaminergic (DA) neurons in Parkinson’s Disease (PD) using hiPSC and organoid models. The mechanism of site-specific DA neuron vulnerability in PD is not yet known; insight into these mechanisms will uncover new therapeutic opportunities in PD.
UG3-NS115064S1 Determine vascular cell type-specific susceptibility to SARS-COV-2 and molecular response to the virus in vasculature microphysiological model
This grant supported by supplemental funding through NCATs allowed us to apply our miBrain technoloyg to Determine vascular cell type-specific susceptibility to SARS-COV-2 and molecular response to the virus in vasculature microphysiological model and evaluate effect of current treatment options and combinations on vasculature in microphysiological model via monitoring markers for thrombosis and vascular risk factors