Read the news coverage of our new @natneuro.nature.com paper here: news.weill.cornell.edu/news/2026/07...

Our study is out today in @NatureNeuro! We show that stressed neurons release DNA, activating cGAS–type I interferon signaling and driving inflammation, seizures and mortality in Dravet syndrome. Blocking cGAS disrupts this immune cascade and improves outcomes. www.nature.com/articles/s41...

cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy - Nature Neuroscience

Huang et al. found that stressed neurons release DNA that activates the immune sensor cGAS, driving inflammatory responses that worsen seizures and mortality in Dravet syndrome. Blocking cGAS interrup...

nature.com

Proud of @sarahnaguib.bsky.social for her new co-first author paper in @molneurodegen.bsky.social in collaboration with @blurtonjoneslab.bsky.social & Paz lab. Transplanted iPSC-derived microglia in progranulin KO mice restores pathology, circuitry, & behavior pubmed.ncbi.nlm.nih.gov/42464356/

Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice - PubMed

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading gen...

pubmed.ncbi.nlm.nih.gov

Excited to see this comprehensive review published in Cell by Dr. Holtzman and colleagues, highlighting the latest advances in Alzheimer's disease and outlining key challenges and opportunities for the field! www.cell.com/cell/fulltex...

Recent advances in Alzheimer’s disease: From molecular mechanisms to therapeutic strategies

Alzheimer’s disease is driven by pathological brain changes that progressively impair memory and cognition, with current treatment options being limited. Advances in early, biomarker-based diagnosis a...

cell.com

Preprint alert⚠️: Using HuMiNAX, an in vivo human iPSC neuroimmune chimera model of tauopathy, we show tau seeds drive neuronal loss, PGRN overexpression in microglia lowers inflammation & protects neurons, & a human neuronal lncRNA pathway mediates degeneration www.biorxiv.org/content/10.6...

Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection

Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized...

biorxiv.org

Our new JCI review discusses the cGAS-STING pathway's evolution & molecular roles beyond inflammation & highlights how activation affects glial states, neuronal homeostasis, & BBB integrity, yielding new therapeutic paths in neurodegenerative disease www.jci.org/articles/vie...

Lu et al. profiled >10,000 plasma & CSF samples to uncover how APOE2 & APOE4 confer divergent AD risk. APOE2 protects by sustaining homeostatic & anti-inflammatory signatures before Aβ accumulation, whereas APOE4 proteomic changes respond after pathology www.nature.com/articles/s43...

Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease - Nature Aging

Apolipoprotein E (APOE) is the strongest genetic influence in Alzheimer’s disease (AD). Compared to the most frequent allele, ε3, the ε4 allele increases AD risk, and the ε2 allele is protective. Here...

nature.com

Gan lab takes on Central Park zoo! Groups ideated, wrote and shot 2-4min short videos about intriguing CP zoo lore last Friday. Awesome time storytelling and collaborating with everyone!

In our latest preprint, we show microglia protect against levodopa-induced dyskinesia (LID): microglia-derived sTREM2 acts on TrkB, boosts BDNF-TrkB signaling, and points to plasticity as a potential Parkinson’s/LID therapy biorxiv.org/content/10.64898/2026.05.06.723382v1

Excited to share our spotlight article in Cell Stem Cell on CAR-A astrocyte therapy for Alzheimer’s disease, an innovative approach for in vivo amyloid clearance. We discuss both the promise and the challenges ahead. 🧠 www.sciencedirect.com/science/arti...

CAR-A astrocytes for Alzheimer’s: Promise and challenge

In a recent study in Science, Chen et al. engineer astrocytes with anti-amyloid chimeric antigen receptors (CARs) to enable sustained, antigen-directe…

sciencedirect.com

New in Nature: de Faria et al. show focal white matter lesions trigger remote microglial response to demyelinated neurons in grey matter, which is required for remyelination. Deplete grey matter microglia→repair failures→chronic grey matter inflammation doi.org/10.1038/s415...

Focal white matter lesions drive grey matter inflammation and synapse loss - Nature

A transient grey matter microgliosis is required for remyelination, the failure of which results in a chronic neuroinflammatory state seen in neurodegenerative disorders.

doi.org

Paquet lab addresses iPSC limitation: new line with endogenous P301L/S320F 4R tau develops age-related tauopathy phenotypes stem cells typically fail to model. Platform shows pathological tau aggregation for more precise tauopathy research & drug screening www.science.org/doi/10.1126/...

A human iPSC model of tauopathies engineered for 4R tau isoform expression endogenously develops late-stage neuronal tau pathology

A human iPSC–derived tauopathy model endogenously recapitulates late-stage pathology and enables translational applications.

science.org

MAPT p.R406W disrupts autophagy–lysosome pathway, impairing Tau degradation. Mutant neurons accumulate Tau/pTau in lysosomes, impairing motility, autophagosome fusion, & clearance. Autophagy enhancement lowers Tau & restores degradation but doesn't rescue trafficking www.nature.com/articles/s41...

A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia - Nature Communications

Researchers show that a disease-causing Tau mutation disrupts the autophagy-lysosome pathway in human neurons, leading to Tau accumulation, and that enhancing autophagy can partially restore protein c...

nature.com

The 13th Annual Appel Symposium on Mar 24 spotlighted the interconnectedness of neurodegenerative diseases. Drs. Sreeganga Chandra (Yale), Eddie Lee (UPenn), & Anna Orr (Appel) gave keynote presentations, preceded by over two dozen trainee posters from Appel & collaborating labs

PanNDA leverages deep proteomics of 2,279 human brain samples in AD, LBD, FTD-TDP-43, PSP, VD, & PD to reveal shared disease mechanisms, spotlighting GPNMB (microglial/lysosomal activation) & NPTX2 (synaptic regulation). Paper: www.cell.com/cell/fulltex.... Data: penglab.shinyapps.io/pannda.

Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures

A pan-neurodegeneration atlas built from multilayer, deep proteomics of 2,279 brain samples across 6 major diseases integrates whole proteome, detergent-insoluble proteome, and posttranslational modif...

cell.com

18 protein panel captures CSF microglia innate immune & cellular recruitment dynamics across AD stages, from preclinical to dementia. Protein profiles track disease progression & could serve as biomarkers for microglia-directed therapeutic interventions link.springer.com/article/10.1...

Microglia protein profiles in CSF across Alzheimer’s disease clinical stages - Nature Aging

Microglia are implicated in the progression of Alzheimer’s disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can ...

link.springer.com

Key insights for microglial therapeutic strategies: Phase 2 trial of TREM2 agonistic antibody AL002 in early AD reduced soluble TREM2 & increased osteopontin in CSF but failed primary cognitive endpoint. ARIA-like MRI abnormalities observed www.nature.com/articles/s41...

The TREM2 agonistic antibody AL002 in early Alzheimer’s disease: a phase 2 randomized trial - Nature Medicine

In this phase 2, randomized trial in early Alzheimer’s disease, the TREM2 agonistic antibody AL002 showed target engagement but did not meet the primary endpoint of change from baseline in Clinical De...

nature.com

New in Science, Cao lab created a single-cell atlas spanning 21 mouse tissues over 3 age groups. Analysis shows broad changes in cellular composition, chromatin accessibility, & transcription factors in immune cells particularly & major sex differences www.science.org/doi/10.1126/...

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging

To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and...

science.org

Congratulations, Nessa Foxe, on receiving the Frank & Blanche Mowrer Memorial 2025-2026 WCGS Merit Fellowship! Nessa is a graduate student in our lab & this award recognizes her for her outstanding productivity & academic record. We couldn't be more proud!

Excited to share our new preprint showing cGAS mediates innate immune activity in TDP-43 proteinopathy. Pharmacological inhibition of cGAS restores microglial function, corrects RNA mis-splicing, & protects motor neurons across human iPSC & mouse models of ALS www.biorxiv.org/content/10.6...

McGavern lab discovers dural venous sinuses are active neuroimmune interfaces. Fenestrated endothelial cells dynamically open/close borders (RAMP2 dependent) to balance fluid exchange with immune cell trafficking. Disruption compromises antiviral immunity www.nature.com/articles/s41...

Highly dynamic dural sinuses support meningeal immunity - Nature

Microscopic imaging and biochemical studies show that sinuses in mouse and human form a highly dynamic surface that regulates fluid movement and immune cell surveillance via RAMP1-dependent regul...

nature.com

Lu lab shows tumor-derived cystatin-C attenuates AD amyloid pathology by acting as molecular glue between microglial TREM2 & amyloid oligomers. This study links cancer biology & AD, spotlighting therapies aimed at clearing existing amyloid plaques www.cell.com/cell/fulltex...

Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2

Peripheral cancer inhibits amyloid pathology and rescues cognition of Alzheimer’s disease through secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates TREM2 in microglia and e...

cell.com

PtdIns(3,5)P2 identified as endogenous lipid ligand of STING, cooperating with cGAMP to promote STING oligomerization, ER-Golgi trafficking, & TBK1 activation. PIKfyve–PtdIns(3,5)P2–STING axis is critical lipid-based mechanism for innate immune signaling www.nature.com/articles/s41...

PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling - Nature

Phosphatidylinositol 3,5-bisphosphate is a ligand of STING and, together with cGAMP, induces STING activation and innate immune responses.

nature.com

We identify microglial cGAS-STING-IFN signaling as a key accelerator of drug-refractory epilepsy in Dravet model. Neuronal hyperexcitability releases DNA that activates microglial cGAS. Pharmacologic cGAS inhibition reduces heat-induced seizures & premature mortality www.biorxiv.org/cgi/content/...

DeepMind debuts AlphaGenome to predict functional genomic features from DNA sequences at single-base resolution. Capturing long-range context, AlphaGenome excels at estimating how genetic variants affect gene expression, splicing, & chromatin accessibility www.nature.com/articles/s41...

Advancing regulatory variant effect prediction with AlphaGenome - Nature

AlphaGenome, a deep learning model that inputs 1-Mb DNA sequence to predict functional genomic tracks at single-base resolution across diverse modalities, outperforms existing models in variant effect...

nature.com

New study in Nat Neurosci finds TGFβ signaling is crucial for maintaining microglial resilience to myelin degeneration in the dorsal column of the spinal cord during aging & emergence of TGFβ signaling-sensitive microglial & disease-associated oligodendrocyte subsets www.nature.com/articles/s41...

TGFβ signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration - Nature Neuroscience

Zhu et al. find that aging causes region-specific myelin damage in the spinal cord, which is counteracted by enhanced TGFβ signaling in microglia, revealing a protective mechanism for healthy aging.

nature.com

Excited to share our new study identifying soluble DLK1 as a novel microglia-derived senescence factor. sDLK1 induced hypomyelination, oligodendrocyte dysfunction, & altered neuronal activity in iPSC-derived neurons @gladstoneinst.bsky.social www.biorxiv.org/content/10.6...

Proud to announce our collaboration with @blurtonjoneslab.bsky.social & the Paz lab showing that transplanted human iPSC-derived microglia in a PGRN KO mouse model restores progranulin in microglia and rescues pathology, circuitry, and behavior. Preprint out now: www.biorxiv.org/cgi/content/...

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading gen...

biorxiv.org

🌲Season’s greetings from the Gan Lab!🌲 Warm wishes for a restful, connected, & rejuvenating turn of the year. For a glimpse into our lab life and research this year, check out: www.ganlab.org

AD genetic risk links microglial immunity and cholesterol. Our new BioRxiv study identifies CH25H-derived 25-HC as a toxic lipid downstream of cGAS–STING–IFN that drives tau spread, inflammation, and neurodegeneration, offering a tractable therapeutic pathway. www.biorxiv.org/cgi/content/...

STING_IFN_CH25H lipid axis links innate immune activation to tau pathology

Genetic risk for Alzheimers disease is strongly enriched in pathways governing microglial activation and cholesterol metabolism, yet how these processes converge to drive neurodegeneration remains unc...

biorxiv.org