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.

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 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...

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...

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

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...

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.

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 ...

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...

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...

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...

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...

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/...

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...

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...

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...

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...

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...

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.

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...

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/...

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...

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...

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.

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...

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...

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...

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/...

🌲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

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...

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/...

Congratulations, Dr. Caitlin Castagnola! Last Friday, Dr. Castagnola defended her thesis on microglia-neuron interactions. Her humble manner, as always, belied the magnitude of work she’s accomplished in the Gan lab. We are so proud of her and excited for all her future chapters!🥳👩‍🔬🧪

DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice - Molecular Neurodegeneration Background Pathogenic tau accumulation drives neurodegeneration in Alzheimer’s disease (AD). Enhancing the aging brain’s resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (...

Our new study in @molneurodegen.bsky.social shows that microglial DAP12 controls tau buildup and drives myelin loss by mediating a harmful tau-induced SLIT2 signal from neurons to oligodendrocytes link.springer.com/article/10.1...

Protective ApoE variants support neuronal function by effluxing oxidized phospholipids Ralhan et al. show that ApoE2 and ApoE3 Christchurch on lipid particles efflux oxidized phospholipids from neurons via the ABCA7 transporter. This reduces the burden of oxidized lipids, which improves...

New study in Neuron: ApoE2 and ApoE3 Christchurch-containing lipid particles protect neurons from ferroptosis by effluxing oxidized lipids through ABCA7. This rescues lysosomal defects, shields ApoE4 hippocampi from lipid toxicity, and restores neural activity www.cell.com/neuron/abstr...

A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease - Nature Neuroscience Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative micro...

New study from Jiang group gives clues to Down syndrome patients' resilience to AD: a DS-linked myeloid mutation (CSF2RB A455D) protects engrafted human microglia against tau by suppressing harmful IFN signaling, boosting phagocytosis, & reducing microglial senescence www.nature.com/articles/s41...

🍁Feeling grateful. Happy Thanksgiving from the Gan lab & Appel Institute!🍁

Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment Clinical evidence from AD patients reveals an association between impaired CCKBR-Gq signaling and disease severity, guiding structure-based design of a Gq-biased agonist that rescues memory and pathol...

A study from the Sun lab reveals that biased CCKBR–Gq/Gi signaling regulates AD pathology & a synthesized CCKBR–Gq agonist (3r1) provides therapeutic benefits by upregulating ADAM10 & PLCB4. This work highlights CCKBR biased signaling as a promising drug target for AD
www.cell.com/cell/fulltex...

Targeting formyl peptide receptor 1 reduces brain inflammation and neurodegeneration Multiple sclerosis (MS) progresses through brain region–specific inflammation and degeneration, with poorly defined mechanisms. In individuals with MS, we identified increased expression of formyl pep...

New in Science!: Microglial FPR1 is a CNS-specific driver of demyelination. Deletion in MG or CNS macrophages protects against myelin loss, while peripheral deletion helps only partly. CNS-penetrant FPR1 antagonist (T0080) reduces ROS, inflammation & disease severity www.science.org/doi/10.1126/...

Thrilled to publish our new study on #mitochondrial ROS coming from complex III, revealing this key site in #astrocytes 🎯as a crucial immunometabolic signal transducer🤯 and potential therapeutic target for #dementia #FTD 💊 rdcu.be/eOc0m 👈💪 Great commentary by H. Pan and F. Yin🤩! tinyurl.com/4hdytw4c

TDP-43 loss induces cryptic polyadenylation in ALS/FTD - Nature Neuroscience The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an ...

Two separate studies from Gitler & Fratta labs reveal nuclear loss of TDP-43 disrupts RNA processing by altering alternative 3′ end cleavage & polyadenylation. They uncover new molecular signatures & shed new light on TDP-43 pathology
www.nature.com/articles/s41...
www.nature.com/articles/s41...

TDP-43 loss brings RNA to a twist ending - Nature Neuroscience In amyotrophic lateral sclerosis (ALS), nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 cause widespread dysregulation of mRNA splicing. Two recent studies have now rev...

New article @natneuro.nature.com by @yaleneuro.bsky.social Suzhou Yang & @kavliatyale.bsky.social Postdoc Fellow @zhenlei.bsky.social, highlighting studies by @frattalab.bsky.social Gitler & La Spada labs on the role of TDP-43 on mRNA 3' end in ALS @yalerna.bsky.social www.nature.com/articles/s41...

A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that na...

Fascinating study from the Mao & Jiang lab: four amino acid residues unique to naked mole-rat cGAS, but absent in humans, are critical for efficient DNA repair, delaying aging and expanding life span. www.science.org/doi/epdf/10....