2. Academic Validation
  3. Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease

Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease

  • Cell Rep. 2024 Dec 24;43(12):114982. doi: 10.1016/j.celrep.2024.114982.
Guoqiang George Sun 1,  Cheng Wang 1,  Randall C Mazzarino 2,  Paula Andrea Perez-Corredor 2,  Hayk Davtyan 3,  Mathew Blurton-Jones 3,  Francisco Lopera 4,  Joseph F Arboleda-Velasquez 2,  Yanhong Shi 5
Affiliations

Affiliations

  • 1 Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
  • 2 Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
  • 3 Department of Neurobiology & Behavior, Institute for Memory Impairments & Neurological Disorders and Sue & Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA.
  • 4 Grupo de Neurociencias de la Universidad de Antioquia, Medellin 050010, Colombia.
  • 5 Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA. Electronic address: yshi@coh.org.
PMID: 39612244 DOI: 10.1016/j.celrep.2024.114982
Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by extracellular amyloid plaques and neuronal Tau tangles. A recent study found that the APOE3 Christchurch (APOECh) variant could delay AD progression. However, the underlying mechanisms remain unclear. In this study, we established neuron-microglia co-cultures and neuroimmune organoids using isogenic APOE3 and APOECh microglia derived from human induced pluripotent stem cells (hiPSCs) with PSEN1 mutant neurons or brain organoids. We show that APOECh microglia are resistant to Aβ-induced lipid peroxidation and Ferroptosis and therefore preserve the phagocytic activity and promote pTau clearance, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia. Moreover, we show that an apoE mimetic peptide can mimic the protective effects of APOECh microglia. These findings demonstrate that the APOECh microglia plays a causal role in microglial neuroprotection, which can be exploited for therapeutic development for AD.

Keywords

APOE Christchurch; CP: Neuroscience; Tau; brain organoids; ferroptosis; iPSCs; induced pluripotent stem cells; lipid droplet; lipid peroxidation; microglia; phagocytosis; presenilin; resilience.

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