Gan Lab

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....

Lewy body dementia promotion by air pollutants Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. In this work, we showed in a cohort of 56.5 million individuals across the United States that fine p...

Mao, Han & Dawson labs reveal air pollutant PM2.5 triggers αSyn misfolding, forming a pathogenic strain (PM-PFF) that drives Lewy body dementia. This study illuminates the link between air pollution & neurodegenerative disease, offering insights for public health
www.science.org/doi/10.1126/...

Multiscale proteomic modeling reveals protein networks driving Alzheimer’s disease pathogenesis Multiscale proteomic network modeling of Alzheimer's disease integrates large-scale proteomic and genetic data from vulnerable brain regions and reveals key driver proteins such as AHNAK within a glia...

Collaborative work from Zhang, Cai & Peng labs identifies a glia-neuron protein co-expression subnetwork as a central driver of AD from multiscale genetic and proteomic analyses. AHNAK emerges as a key astrocytic driver whose downregulation reduces pTau & Aβ levels. www.cell.com/cell/fulltex...

Rod-shaped microglia interact with neuronal dendrites to attenuate cortical excitability during TDP-43-related neurodegeneration While microglial activation is a hallmark in neurodegeneration, the specific role of microglia in disease-related cortical excitability remains unknown. Xie et al. reveal that rod-shaped microglia for...

Wu lab discovers early neuronal hyperactivity in TDP-43 induces rod-shaped microglia, which attenuates cortical hyperactivity, suggesting a neuroprotective role. Coincidentally, TREM2 signaling also promotes rod-shaped MG & neuroprotection. www.cell.com/immunity/abs...

Neurons sequester the cholesterol-inhibiting TFEB in oligodendrocyte cytoplasm to safeguard myelination and neural function Zhang et al. identify TFEB as a molecular link that connects extrinsic neuronal cues to intrinsic oligodendrocyte transcriptional programs. TFEB directly binds to and represses numerous cholesterol bi...

New study from Yu & Sun identifies TFEB as a molecular link between neurons & oligodendrocytes (OL) in myelination. Neuronal signals trap TFEB in OL's cytoplasm, keeping TFEB from entering nucleus & repressing cholesterol biosynthesis genes, which causes hypomyelination
www.cell.com/cell-reports...

Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer’s disease Microglia-mediated neuroinflammation drives Alzheimer's disease (AD) pathogenesis, yet the underlying mechanism is poorly understood. Song et al. demonstrate that toxic amyloid-β induces oxidation and...

Interesting study from Xu, Zhang & Mo labs: oxidized mtDNA can transform into Z-DNA & activate ZBP1–RIPK1–dependent inflammation in AD microglia. This highlights ZBP1–RIPK1 as a key regulatory axis of neuroinflammation & offers novel insights on AD inflammatory networks www.cell.com/immunity/ful...

🏆🏆🏆 CONGRATULATIONS to the winner of the PBL Assay Science Best Speaker Award Sarah Naguib @sarahnaguib.bsky.social

Title: Elucidating the neuroprotective mechanisms of human microglial replacement therapy in FTD and PD

Thank you PBL Assay Science for sponsoring the award

The Kolachama Lab is tackling the PET scan bottleneck in Alzheimer’s diagnosis with an AI model that predicts amyloid-β & tau status from 12,185 patients across 7 cohorts, offering a scalable alternative for pre-screening & guiding PET imaging. www.nature.com/articles/s41...

Lithium deficiency and the onset of Alzheimer’s disease - Nature Lithium has an essential role in the brain and is deficient early in Alzheimer’s disease, which can be recapitulated in mice and treated with a novel lithium salt that restores the physiological level...

Exciting finding: Endogenous lithium is essential for brain health and its deficiency contributes to the onset and progression of Alzheimer’s disease, by activating GSK3β—leading to impaired Aβ clearance and synapse loss
🧠 Led by Dr. Bruce Yankner @harvardmed.bsky.social
🔗 doi.org/10.1038/s415...

Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS UFMylation is the post-translational modification of Ubiquitin Fold Modifier1 (UFM1) applied to substrate proteins. Blazev et al. develop an antibody-based enrichment approach followed by LC-MS/MS to ...

By developing an antibody-based method using mass spec, this study uncovered >200 UFMylation sites across mouse tissues—including on myosin. Myosin UFMylation is elevated in skeletal muscle from people with ALS, suggesting in vivo UFMylation is more dynamic than expected www.cell.com/cell-reports...

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates Stress granules promote TDP-43 aggregation via intra-condensate demixing, a pathway triggered by its up-concentration and oxidation within condensates. Blocking this demixing pathway prevents TDP-43 a...

Fascinating study from Hyman, Alberti & Mittal labs reveals how stress granules promote TDP-43 aggregation through intra-condensate demixing driven by Cys oxidation & hydrophobic patch contacts, marking the crucial role of stress granules & opening new doors for therapy.
www.cell.com/cell/fulltex...

Cell-type-directed network-correcting combination therapy for Alzheimer’s disease A multi-cell-type drug discovery strategy targeting dysregulated gene networks in neurons and glia identified letrozole and irinotecan as a combination therapy that significantly improved memory and r...

The Sirota & Huang labs identified a novel letrozole–irinotecan combination therapy that improves memory and reduces pathology in Alzheimer's disease models—showcasing a transformative drug discovery approach rooted in human transcriptomics and real-world clinical data www.cell.com/cell/fulltex...

‪Thrilled to collaborate with @hagentilgner.bsky.social on this study! Looking forward to more exciting projects together.

Combined single-cell profiling of chromatin–transcriptome and splicing across brain cell types, regions and disease state - Nature Biotechnology Joint profiling of chromatin and splicing in the brain uncovers shared and distinct patterns.

New from Tilgner & Gan labs: Using ScISOr–ATAC, we found that splicing patterns differ across cell states within the same cell type in frozen primate cortex, and that oligodendrocytes in Alzheimer’s show high dysregulation in splicing & chromatin. Read more: www.nature.com/articles/s41...

Huge thanks and congratulations to @sarahnaguib.bsky.social, @chloelopezlee.bsky.social @ertorres.bsky.social, the rest of the Gan lab, and our amazing collaborators who made this work possible!

The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a cau…

🚨Our new paper is out!🚨 We uncover a protective mechanism of the rare APOE3 Christchurch (R136S) mutation against tauopathy—by suppressing microglial cGAS–STING–interferon (IFN) pathway, a key inflammatory axis triggered by tau. www.sciencedirect.com/science/arti...

Our 12th Annual Appel Symposium was a huge success! Record attendance, insightful faculty speakers, and a vibrant poster session sparked meaningful conversations and highlighted the innovative research at WCM. A sincere thank you to all who attended and the WCM teams who made this event possible.

Congratulations, Akida Abulimit @akidaabu.bsky.social, for winning 3rd place in Poster Presentation at the Weill Cornell Graduate Program in Physiology, Biophysics and Systems Biology 2024 Retreat!

Events - NYAS Bringing together experts and partners from academia, industry, and government, the Academy convenes conferences, symposia, and workshops that provide a neutral forum for the exchange of information o...

Our lab enjoyed the exciting scientific advancements & fruitful discussions at the NYAS Therapeutic Approaches to Protein Misfolding in Neurodegenerative Disease conference this week! Dr. Gan presented on enhancing resilience against tau alongside other stellar speakers. www.nyas.org/shaping-scie...

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microgli…

Exciting work @blurtonjoneslab.bsky.social: CRISPR-engineered iPSC-microglia use the plaque-responsive CD9 promoter to deliver Aβ-degrading neprilysin across the brain-- reducing plaques, inflammation & synaptic loss. A promising new cell therapy platform for AD www.sciencedirect.com/science/arti...

Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease - Nature Medicine Plasma eMTBR-tau243 is a specific biomarker of tau tangles in Alzheimer’s disease and enables the detecting and tracking of Alzheimer’s clinical impairment.

According to researchers Kanta Horie, Gemma Salvadó, Rama Koppisetti, Oskar Hansson, Randall Bateman, et al. newly developed blood test for #Alzheimers not only aids in diagnosis of Alzheimer's but also indicates how far it has progressed. Learn More in Nature Medicine
www.nature.com/articles/s41...