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Jorfi, Mehdi

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Jorfi

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Mehdi

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Jorfi, Mehdi

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2018 - 201912020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.44cef0a9-1670-409e-8ca0-765c93d1f5e9

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    Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
    (Springer Science and Business Media LLC, 2021-07-14) McAlpine, Cameron; Park, Joseph; Griciuc, Ana; Kim, Eunhee; Choi, Se Hoon; Iwamoto, Yoshiko; Kiss, Máté G.; Christie, Kathleen; Vinegoni, Claudio; Poller, Wolfram; Mindur, John; Chan, Christopher; He, Shun; Janssen, Henrike; Wong, Lai Ping; Downey, Jeffrey; Singh, Sumnima; Anzai, Atsushi; Kahles, Florian; Jorfi, Mehdi; Feruglio, Paulo; Sadreyev, Ruslan; Weissleder, Ralph; Kleinstiver, Benjamin; Nahrendorf, Matthias; Tanzi, Rudolph; Swirski, Filip
    Communication within the glial cell ecosystem is essential to neuronal and brain health1–3. The influence of glial cells on β-amyloid (Aβ) and neurofibrillary tau accumulation and clearance in Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) reprograms microglia to ameliorate AD pathology. Upon recognition of Aβ deposits, microglia augment IL-3Rɑ, IL-3’s specific receptor, rendering them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional reprograming of microglia endowing them with an acute immune response program, enhanced motility, and the capacity to cluster and clear Aβ and tau aggregates. These changes restrict AD pathology and cognitive decline. This study identifies IL-3 as a critical mediator of astrocyte-microglia crosstalk and a node for therapeutic intervention in AD.
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    Human Neurospheroid Arrays for In Vitro Studies of Alzheimer’s Disease
    (Nature Publishing Group UK, 2018) Jorfi, Mehdi; D’Avanzo, Carla; Tanzi, Rudolph; Kim, Doo Yeon; Irimia, Daniel
    Neurospheroids are commonly used for in vitro disease modeling and drug screening. However, the heterogeneity in size of the neurospheroids mixtures available through current methods limits their utility when employed for basic mechanistic studies of neurodegenerative diseases or screening for new interventions. Here, we generate neurospheroids from immortalized neural progenitor cells and human induced pluripotent stem cells that are uniform in size, into large-scale arrays. In proof of concept experiments, we validate the neurospheroids array as a sensitive and robust tool for screening compounds over extended time. We show that when suspended in three-dimensional extracellular matrix up to several weeks, the stem cell-derived neurospheroids display extensive neurite outgrowth and extend thick bundles of dendrites outward. We also cultivate genetically-engineered stem cell-derived neurospheroids with familial Alzheimer’s disease mutations for eight weeks in our microarray system. Interestingly, we observed robust accumulation of amyloid-β and phosphorylated tau, key hallmarks of Alzheimer’s disease. Overall, our in vitro model for engineering neurospheroid arrays is a valuable tool for studying complex neurodegenerative diseases and accelerating drug discovery.