In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons
Ramsey Najm,
Kelly A. Zalocusky,
Misha Zilberter,
Seo Yeon Yoon,
Yanxia Hao,
Nicole Koutsodendris,
Maxine Nelson,
Antara Rao,
Alice Taubes,
Emily A. Jones,
Yadong Huang
Affiliations
Ramsey Najm
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
Kelly A. Zalocusky
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Gladstone Center for Translational Advancement, San Francisco, CA 94158, USA
Misha Zilberter
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Seo Yeon Yoon
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Yanxia Hao
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Gladstone Center for Translational Advancement, San Francisco, CA 94158, USA
Nicole Koutsodendris
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
Maxine Nelson
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
Antara Rao
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
Alice Taubes
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
Emily A. Jones
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
Yadong Huang
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Center for Translational Advancement, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author
Summary: Despite its clear impact on Alzheimer’s disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single-nucleus RNA sequencing (snRNA-seq), we identify key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also find that Aβ from transplanted human neurons forms plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.
