Gan Lab

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...

Oxidation of retromer complex controls mitochondrial translation - Nature Systematic base-editing and computational screens identify specific cysteine residues on VPS35 in the retromer complex as key sensors that decrease mitochondrial translation in response to reactive ox...

Fascinating study from Nature reveals crosstalk between mitochondrial translation, ROS activity, and the membrane retromer complex. www.nature.com/articles/s41...

A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease - Nature Medicine The ratio between the levels of two synaptic proteins in cerebrospinal fluid predicts future cognitive resilience versus decline among presymptomatic individuals and individuals with early Alzheimer’s...

A CSF proteomics study in Nature Medicine of 3,397 individuals identified synaptic proteins YWHAG:NPTX2 as key correlates of cognitive impairment in AD, highlighting synapse dysfunction as a core driver of AD dementia. #Alzheimers #Proteomics #Neurodegeneration www.nature.com/articles/s41...

Big congratulations to Dr. Celeste Parra Bravo! 🎓 Last Tues, 3/25, Dr. Parra Bravo defended her thesis with command and grace. Next, she’s headed to a postdoc in the Rosato lab at Dartmouth. We’re so proud of all she’s accomplished and can’t wait to see her continued contributions to science!🧪🔬🧠