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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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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.

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Dr. Ghazaleh Eskandari-Sedighi highlighted by UCI MIND

Talented UCI MIND Trainee awarded Research Fellowship

Ghazaleh Eskandar-Sedighi, PhD, is a postdoctoral fellow, supervised by Mathew Blurton-Jones, PhD, professor of Neurobiology and Behavior in the Charlie Dunlop School of Biological Sciences. Dr. Eskander-Sedighi was recently awarded a prestigious Postdoctoral Fellowship in Alzheimer’s disease research from the BrightFocus Foundation. Ghazeleh’s research focuses on leveraging human stem cell-derived microglia and chimeric animal models to investigate protective microglial responses in the context of Alzheimer’s disease (AD). Her BrightFocus Foundation project specifically aims to take advantage of novel, multi-faceted stem cell and chimeric mouse models to study the impact of the protective microglial ApoE3 Christchurch mutation on disease pathogenesis in a novel mouse model of AD with combined amyloid and tau pathologies. Considering the significant advancements in the field of microglia-based therapeutics, the results from this 2-year, $200,000 fellowship could help the field clarify the potential therapeutic role of protective variants like APOE Christchurch against AD. Congratulations Ghazeleh!