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Weerakkody and Sabelstrom et al. publish in Science Translational Medicine

Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer’s disease

The Alzheimer’s disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. In this study, co-led by researchers from Denali Therapeutics and Blurton-Jones Lab, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.

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Coburn and Eskandari-Sedighi et al. Publish in Alzheimer’s & Dementia

Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer’s disease pathologies in vivo

Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer’s disease (AD) remains unclear. We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling. The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct “rod” morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro. We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.

Highlights

  • Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD.
  • Combined Alzheimer’s disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia.
  • The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration.
  • Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.
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Chadarevian et al. publish in Molecular Therapy

CSF1R inhibitor-resistant model for CNS-wide microglia replacement strategies

Recent advances in cell-based therapies have demonstrated therapeutic safety and efficacy for a variety of diseases. However, significant challenges remain in their development for the treatment of neurological disorders. Preclinical studies have explored microglial replacement strategies utilizing bone marrow transplantation and CSF1R inhibitor (CSF1Ri) treatment. However, these approaches often require highly invasive strategies and result in engrafted cells that remain transcriptionally and functionally distinct from microglia. To assess less-invasive microglia replacement strategies capable of preserving microglial ontogeny, we developed a Csf1r-G793A knockin mouse. We found that G793A mice develop typical microglial densities and peripheral hematopoietic populations, which exhibit broad CSF1Ri resistance enabling widespread microglia replacement following direct intraparenchymal injection or bone marrow transplantation. Furthermore, we demonstrate that widespread microglia replacement can be achieved via less-invasive intracisternal delivery of CSF1Ri-resistant murine and induced pluripotent stem cell (iPSC)-derived human microglia. Together with the accompanying study by Lombroso and colleagues, our findings demonstrate that G793A mice provide a robust and broadly applicable source of engraftable donor microglia and peripheral macrophages for the preclinical investigation of microglia replacement strategies.

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Dr. Chadarevian awarded 2025 Tom Angell Post Doctoral Fellowship Award

Awarded annually at the Office of Inclusive Excellence’s Mentoring for Achievement and Excellence event, this fellowship is intended to honor Tom Angell’s contributions as the UCI Graduate Counselor to graduate student wellness and retention. Recipients are selected for having demonstrated outstanding mentorship by going above and beyond their normal duties to create new opportunities to mentor UCI students. This year, Dr. Jean Paul Chadarevian was selected as the Tom Angell Postdoctoral Scholar and recognized by the Office of Inclusive Excellence.

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Blurton-Jones Lab attends inaugural 2025 Gordon Research Conference on Alzheimer’s Disease 

Post doctoral fellows Ghazaleh Eskandari-Sedighi and Jean Paul Chadarevian attend the 2025 Alzheimer’s Disease: Multimodal Approaches to Mechanisms and Therapeutic Targets. In attendance were former MBJ lab members Emma Danhesh and Dr. Christel Claes. During the Functional Genomics and Alzheimer’s Disease session led by Dr. Celeste Karch, Dr. Ghazaleh presented “A Chimeric Mouse Model of Alzheimer’s Disease With Combined Amyloid and Tau Pathologies to Study Protective Human Microglia Responses in the Context of Disease“. Session included discussions on Systems Biology and Alzheimer’s Disease, Neuroimaging and Alzheimer’s Disease Models and Endophenotypes, AI and Machine Learning in AD, Epigenetics and Multi-Omics, Population and Sex Differences in Alzheimer’s Disease, and Therapeutic Approaches. Congratulations to chairs, Dr. Olivier Lichtarge and Dr. Towfique Raj, on an outstanding conference!

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Blurton-Jones Lab presents at ISSCR 2025 “Illuminating the Future”

Dr. Jean Paul Chadarevian presents “Engineering iPSC-derived Microglia for Immune Cell-based Therapies for Neurological Disorders” at the ISSCR 2025 Annual Meeting held in Hong Kong from 11-14 June 2025. His session Expanding Therapeutics through Stem Cells and Reprogramming was chaired by Dr. Athanasia D. Panopoulos of Cedars-Sinai Medical Center, and included concurrent talks from Dr. Maria Pia Cosma, Professor at the Centre for Genomic Regulation, and Dr. Pentao Liu, Professor of the University of Hong Kong.

The Guojun Bu Laboratory also hosted Dr. Chadarevian at the Hong Kong University of Science and Technology.

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Dr. Chadarevian awarded Larry L. Hillblom Foundation Postdoctoral Fellowship

The University of California, Irvine Institute for Memory Impairments and Neurological Disorders (UCI MIND) is proud to announce that postdoctoral fellow Jean Paul Chadarevian, PhD, has been awarded a prestigious grant from the Larry L. Hillblom Foundation. The three-year, $225,000 award will support Dr. Chadarevian’s innovative research into the role of peripheral immune cells in the development and progression of Alzheimer’s disease (AD). Working in the laboratory of Dr. Mathew Blurton-Jones, Professor of Neurobiology and Behavior at UCI, Dr. Chadarevian will investigate how immune cells that originate outside the brain infiltrate it and contribute to the disease’s pathology.

Read more here.