bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–08–10
29 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.
  2. Swapping microglia to treat ALSP.
  3. Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience.
  4. Spatiotemporal lipidomics in living tissue.
  5. Does lithium deficiency contribute to Alzheimer's disease?
  6. The multifunctional immune system.
  7. Sex differences in tissue-specific immunity and immunology.
  8. DIY innate immune sensing: Crafting fresh DNA to detect viruses.
  9. RNA N-glycosylation enables immune evasion and homeostatic efferocytosis.
  10. Parent-of-origin effects found for gene variants that affect human growth and metabolism.
  11. Whole-genome sequencing of 490,640 UK Biobank participants.
  12. New hope for Alzheimer's: lithium supplement reverses memory loss in mice.
  13. TLR4+group 2 innate lymphoid cells contribute to persistent type 2 immunity in airway diseases.
  14. Long-range enhancers rely on LHX motifs.
  15. EBV induces CNS homing of B cells attracting inflammatory T cells.
  16. CSF1R regulates monocyte subset differentiation and intracellular metabolism.
  17. Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
  18. The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.
  19. Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
  20. Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
  21. Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.
  22. Lithium deficiency and the onset of Alzheimer's disease.
  23. Regional heterogeneity of the blood-brain barrier.
  24. Cell surface crowding is a tunable energetic barrier to cell-cell fusion.
  25. Design of soluble Notch agonists that drive T cell development and boost immunity.
  26. Eating ultra-processed foods could make it harder to lose weight.
  27. Neurons feed tumors.
  28. A programmed decline in ribosome levels governs human early neurodevelopment.
  29. Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.
  1. Science. 2025 Aug 07. 389(6760): eads3204
    Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.
    Michelle E Pizzo, Edward D Plowey, Nathalie Khoury, Wanda Kwan, Jordan Abettan, Sarah L DeVos, Claire B Discenza, Timothy Earr, David Joy, Ming Lye-Barthel, Elysia Roche, Darren Chan, Jason C Dugas, Kapil Gadkar, Stefan Hamann, René Meisner, Jennifer Sebalusky, Ana Claudia Silva Amaral, Isabel Becerra, Roni Chau, Johann Chow, Allisa J Clemens, Mark S Dennis, Joseph Duque, Laura Fusaro, Jennifer A Getz, Mihalis S Kariolis, Do Jin Kim, Kendra J Lechtenberg, Amy Wing-Sze Leung, Arash Moshkforoush, Hoang N Nguyen, Emmanuel S Ojo, Elliot R Thomsen, Vanessa O Torres, Pascal E Sanchez, Lu Shan, Adam P Silverman, Zachary K Sweeney, Hilda Solanoy, Raymond Tong, Meredith E Calvert, Ryan J Watts, Robert G Thorne, Paul H Weinreb, Dominic M Walsh, Joseph W Lewcock, Thierry Bussiere, Y Joy Yu Zuchero.
      Amyloid-related imaging abnormalities (ARIA), side effects of anti-amyloid drugs seen in magnetic resonance imaging of the brain, are a major safety concern in patients with Alzheimer's disease. We developed an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) for brain delivery of anti-amyloid-β protein (anti-Aβ) using asymmetrical Fc mutations (ATVcisLALA) that mitigates TfR-related liabilities and retains effector function when bound to Aβ. Administration of ATVcisLALA:Aβ in mice exhibited broad brain distribution and enhanced parenchymal plaque target engagement. This biodistribution reduced ARIA-like lesions and vascular inflammation. Taken together, ATVcisLALA has the potential to improve the next generation of Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.
    DOI:  https://doi.org/10.1126/science.ads3204
  2. Nat Neurosci. 2025 Aug;28(8): 1577
    Swapping microglia to treat ALSP.
    Rebecca Wright.
      
    DOI:  https://doi.org/10.1038/s41593-025-02047-5
  3. Cell. 2025 Jul 29. pii: S0092-8674(25)00733-0. [Epub ahead of print]
    Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience.
    Zunpeng Liu, Shanshan Zhang, Benjamin T James, Kyriaki Galani, Riley J Mangan, Stuart Benjamin Fass, Chuqian Liang, Manoj M Wagle, Carles A Boix, Yosuke Tanigawa, Sukwon Yun, Yena Sung, Xushen Xiong, Na Sun, Lei Hou, Martin Wohlwend, Mufan Qiu, Xikun Han, Lei Xiong, Efthalia Preka, Lei Huang, William F Li, Li-Lun Ho, Amy Grayson, Julio Mantero, Alexey Kozlenkov, Hansruedi Mathys, Tianlong Chen, Stella Dracheva, David A Bennett, Li-Huei Tsai, Manolis Kellis.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals. We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience. This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.
    Keywords:  Alzheimer's disease; cognitive resilience; epigenomic erosion; epigenomic information; epigenomic stability; epigenomics; exhaustion; microglial activation; regulatory network; single-cell multiomics
    DOI:  https://doi.org/10.1016/j.cell.2025.06.031
  4. Nat Methods. 2025 Aug;22(8): 1622
    Spatiotemporal lipidomics in living tissue.
    Arunima Singh.
      
    DOI:  https://doi.org/10.1038/s41592-025-02790-4
  5. Nature. 2025 Aug 06.
    Does lithium deficiency contribute to Alzheimer's disease?
    Ashley I Bush.
      
    Keywords:  Alzheimer's disease; Brain; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-02255-w
  6. Science. 2025 Aug 07. 389(6760): 586-587
    The multifunctional immune system.
    Sarah Ross, Caroline Ash.
      
    DOI:  https://doi.org/10.1126/science.aea8294
  7. Science. 2025 Aug 07. 389(6760): 599-603
    Sex differences in tissue-specific immunity and immunology.
    Sonia Sharma, Alicia Gibbons, Erica Ollmann Saphire.
      Biological sex exerts a substantial influence on the immune system and immune-related diseases. Males are more susceptible to the acute effects of viral disease and certain cancers, whereas females exhibit a more robust immune response that can make them prone to developing autoimmune complications. We reflect on the emerging appreciation of sex differences-governed by genetics, sex hormones, and environmental factors-in tissue immunity and immunology. Understanding these tissue context-dependent sex differences in the immune system is critical to deciphering the exact mechanisms that determine why women and men experience organ-specific infections, autoimmune or inflammatory diseases, and cancers differently. Only by parsing distinction at the tissue level can the development of personalized and precision immunotherapy approaches be conceived and then achieved.
    DOI:  https://doi.org/10.1126/science.adx4381
  8. Mol Cell. 2025 Aug 07. pii: S1097-2765(25)00610-0. [Epub ahead of print]85(15): 2818-2820
    DIY innate immune sensing: Crafting fresh DNA to detect viruses.
    Erika Valeri, Moritz M Gaidt.
      The innate immune receptor cGAS is geared toward detecting DNA from pathogens. In a recent Cell publication, Lahaye et al.1 discovered that viral infection triggers de novo synthesis of self-DNA-activating cGAS.
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.009
  9. Nature. 2025 Aug 06.
    RNA N-glycosylation enables immune evasion and homeostatic efferocytosis.
    Vincent R Graziano, Jennifer Porat, Marie Dominique Ah Kioon, Ivana Mejdrová, Alyssa J Matz, Charlotta G Lebedenko, Peiyuan Chai, John V Pluvinage, Rafael Ricci-Azevedo, Andrew G Harrison, Skylar S Wright, Xinzheng Wang, Madison S Strine, Penghua Wang, Michael R Wilson, Sivapriya Kailasan Vanaja, Beiyan Zhou, Franck J Barrat, Thomas Carell, Ryan A Flynn, Vijay A Rathinam.
      Glycosylation is central to the localization and function of biomolecules1. We recently discovered that small RNAs undergo N-glycosylation2 at the modified RNA base 3-(3-amino-3-carboxypropyl) uridine (acp3U)3. However, the functional significance of N-glycosylation of RNAs is unknown. Here we show that the N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs. We found that de-N-glycosylation of cell-culture-derived and circulating human and mouse glycoRNA elicited potent inflammatory responses including the production of type I interferons in a Toll-like receptor 3- and Toll-like receptor 7-dependent manner. Furthermore, we show that N-glycans on cell surface RNAs prevent apoptotic cells from triggering endosomal RNA sensors in efferocytes, thus facilitating the non-inflammatory clearance of dead cells. Mechanistically, N-glycans conceal the hypermodified uracil base acp3U, which we identified as immunostimulatory when exposed in RNA. Consistent with this, genetic deletion of an enzyme (DTWD2) that synthesizes acp3U abrogated innate immune activation by de-N-glycosylated small RNAs and apoptotic cells. Furthermore, synthetic acp3U-containing RNAs are sufficient to trigger innate immune responses. Thus, our study has uncovered a natural mechanism by which N-glycans block RNAs from inducing acp3U-dependent innate immune activation, demonstrating how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses.
    DOI:  https://doi.org/10.1038/s41586-025-09310-6
  10. Nature. 2025 Aug 06.
    Parent-of-origin effects found for gene variants that affect human growth and metabolism.
      
    Keywords:  Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-02391-3
  11. Nature. 2025 Aug 06.
    Whole-genome sequencing of 490,640 UK Biobank participants.
    UK Biobank Whole-Genome Sequencing Consortium
      Whole-genome sequencing provides an unbiased and complete view of the human genome and enables the discovery of genetic variation without the technical limitations of other genotyping technologies. Here we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping effort1. This advance deepens our understanding of how genetics associates with disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations and identified novel genetic and clinical insights. Although most associations with disease traits were primarily observed in individuals of European ancestries, strong or novel signals were also identified in individuals of African and Asian ancestries. With the improved ability to accurately genotype structural variants and exonic variation in both coding and UTR sequences, we strengthened and revealed novel insights relative to whole-exome sequencing2,3 analyses. This dataset, representing a large collection of whole-genome sequencing data that is available to the UK Biobank research community, will enable advances of our understanding of the human genome, facilitate the discovery of diagnostics and therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.
    DOI:  https://doi.org/10.1038/s41586-025-09272-9
  12. Nature. 2025 Aug 06.
    New hope for Alzheimer's: lithium supplement reverses memory loss in mice.
    Lynne Peeples.
      
    Keywords:  Alzheimer's disease; Brain; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-02471-4
  13. Nat Commun. 2025 Aug 02. 16(1): 7108
    TLR4+group 2 innate lymphoid cells contribute to persistent type 2 immunity in airway diseases.
    Yan Li, Zaichuan Wang, Su Duan, Xue Wang, Yuling Zhang, Claus Bachert, Nan Zhang, Wei Wang, Sun Ying, Feng Lan, Chengshuo Wang, Luo Zhang.
      Group 2 innate lymphoid cells (ILC2s) directly contribute to local inflammation in type 2 inflammatory airway diseases. Here, we identify ILC2 subsets by single cell RNA sequencing in chronic rhinosinusitis with nasal polyps (CRSwNP) and in a memory inflammatory mouse model. We find that toll-like receptor 4 (TLR4)+ILC2s, with similar markers to their human counterparts, expresse memory cell markers, persist over time, and respond more vigorously to a secondary unrelated antigen challenge in the mouse model. Genetic ablation of TLR4 or blockade by anti-TLR4 antibodies leads to the reduction of IL-13 expression from ILC2s and mucus production in mice. The assay for transposase-accessible chromatin sequencing further confirms the importance of accessible TLR4 gene loci and its down-stream signaling pathway in maintaining trained immunity of TLR4+ILC2s after repeated stimulation by HDM. Taken together, TLR4 has a function in trained immunity maintenance within ILC2s, which may contribute to disease chronicity through a non-specific immunological memory.
    DOI:  https://doi.org/10.1038/s41467-025-62532-0
  14. Nat Genet. 2025 Aug 08.
    Long-range enhancers rely on LHX motifs.
    Tiago Faial.
      
    DOI:  https://doi.org/10.1038/s41588-025-02311-1
  15. Nature. 2025 Aug 06.
    EBV induces CNS homing of B cells attracting inflammatory T cells.
    Fabienne Läderach, Ioannis Piteros, Éanna Fennell, Elena Bremer, Mette Last, Sandra Schmid, Lisa Rieble, Caroline Campbell, Isis Ludwig-Portugall, Lea Bornemann, Alexander Gruhl, Klaus Eulitz, Paul Gueguen, Juliane Mietz, Anne Müller, Gaetana Pezzino, Jürgen Schmitz, Guido Ferlazzo, Josef Mautner, Christian Münz.
      Epidemiological data have identified Epstein-Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS)1. However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH1 cells as well as CD4+ TH17 cells co-migrate to the brain of EBV-infected humanized mice. T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.
    DOI:  https://doi.org/10.1038/s41586-025-09378-0
  16. bioRxiv. 2025 Jul 21. pii: 2025.07.17.665275. [Epub ahead of print]
    CSF1R regulates monocyte subset differentiation and intracellular metabolism.
    Alexandre Gallerand, Johanna Merlin, Zakariya Caillot, Chloé Delaby, Elisa Bord, Jichang Han, Bastien Dolfi, Alexia Castiglione, Sacha Grenet, Maxime Franceschini, Gisèle Jarretou, Fairouz N Zair, Evy Boré, Florian Tuffin, David Dombrowicz, Rodolphe R Guinamard, Gwendalyn J Randolph, Adeline Bertola, Patrick Auberger, Arnaud Jacquel, David A Hume, Jesse W Williams, Marc Bajénoff, Jaap G Neels, Stoyan Ivanov.
      Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6C high ) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6C low ) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6C low monocytes in part by blunting differentiation of Ly6C high monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.
    DOI:  https://doi.org/10.1101/2025.07.17.665275
  17. Nat Commun. 2025 Aug 04. 16(1): 7174
    Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
    Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.
      The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.
    DOI:  https://doi.org/10.1038/s41467-025-62484-5
  18. Nat Cell Biol. 2025 Aug 04.
    The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.
    Mikhail Rudinskiy, Carmela Galli, Andrea Raimondi, Maurizio Molinari.
      Organellophagy receptors control the generation and delivery of portions of their homing organelle to acidic degradative compartments to recycle nutrients, remove toxic or aged macromolecules and remodel the organelle upon physiologic or pathologic cues. How they operate is not understood. Here we show that organellophagy receptors are composed of a membrane-tethering module that controls organellar and suborganellar distribution and by a cytoplasmic intrinsically disordered region (IDR) with net cumulative negative charge that controls organelle fragmentation and displays an LC3-interacting region (LIR). The LIR is required for lysosomal delivery but is dispensable for organelle fragmentation. Endoplasmic reticulum (ER)-phagy receptors' IDRs trigger DRP1-assisted mitochondrial fragmentation and mitophagy when transplanted at the outer mitochondrial membrane. Mitophagy receptors' IDRs trigger ER fragmentation and ER-phagy when transplanted at the ER membrane. This offers an interesting example of function conservation on sequence divergency. Our results imply the possibility to control the integrity and activity of intracellular organelles by surface expression of organelle-targeted chimeras composed of an organelle-targeting module and an IDR module with net cumulative negative charge that, if it contains a LIR, eventually tags the organelle portions for lysosomal clearance.
    DOI:  https://doi.org/10.1038/s41556-025-01728-4
  19. Nat Neurosci. 2025 Aug 06.
    Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
    Eizo Marutani, Maria Miranda, Timothy J Durham, Sharon H Kim, Dreson L Russell, Presli P Wiesenthal, Paul Lichtenegger, Marissa A Menard, Charlotte F Brzozowski, Haobo Li, Gary Ruvkun, Joshua D Meisel, Laura Volpicelli-Daley, Vamsi K Mootha, Fumito Ichinose.
      Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.
    DOI:  https://doi.org/10.1038/s41593-025-02010-4
  20. Nat Commun. 2025 Aug 07. 16(1): 7304
    Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
    Shengnan Li, Zhaoliang Shan, Guochun Zhao, Yuwei Li, Minghui Du, Xiuxiu Ti, Yuxue Gao, Wenting Li, Hui Zuo, Yan Wang, Qing Zhang.
      Mitochondria coordinate with lysosomes to maintain cellular homeomstasis. However, in mitochondrial defect condition, how they communicate is less clear. Here, utilizing dMterf4 RNAi fly model, we find that expression of lysosomal alpha-mannosidase VI (LManVI) is significantly downregulated. Mechanistically, we show that dMterf4 RNAi-triggered mitochondrial defect mediates downregulation of lysosomal LManVI through Med8/Tfb4-E(z)/pho axis, causing impairment of lysosomal function. Reciprocally, downregulation of lysosomal LManVI further decreases many mitochondrial genes expression through downregulation of transcriptional coactivator PGC-1, leading to aggravating the dMterf4 RNAi-mediated mitochondrial defect, suggesting that mitochondrial defect can crosstalk with lysosomes to make mitochondrial status worse in a positive feedback way. Finally, we demarcate that this interaction between mitochondria and lysosomes may be conserved in mammalian cells. Therefore, our findings unveil a communication mechanism between mitochondria and lysosomes in mitochondrial defect case, which provides insights about the treatments of related mitochondrial and lysosomal diseases through modulation of the mitochondria-lysosomes axis.
    DOI:  https://doi.org/10.1038/s41467-025-62147-5
  21. Nat Commun. 2025 Aug 04. 16(1): 7147
    Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.
    Reji Babygirija, Jessica H Han, Michelle M Sonsalla, Ryan Matoska, Mariah F Calubag, Cara L Green, Anna Tobon, Chung-Yang Yeh, Diana Vertein, Sophia Schlorf, Julia Illiano, Yang Liu, Isaac Grunow, Michael J Rigby, Luigi Puglielli, David A Harris, John M Denu, Dudley W Lamming.
      Caloric restriction slows or prevents Alzheimer's disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer's disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting. We find that reducing calories alone improves body weight and glucose tolerance. However, a prolonged fast between meals is necessary for many of the benefits of calorie restriction, including improved insulin sensitivity, reduced Alzheimer's pathology, improved neuroprotective signaling, and improved cognition. Overall, our results suggest that both when and how much we eat may influence the development and progression of Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41467-025-62416-3
  22. Nature. 2025 Aug 06.
    Lithium deficiency and the onset of Alzheimer's disease.
    Liviu Aron, Zhen Kai Ngian, Chenxi Qiu, Jaejoon Choi, Marianna Liang, Derek M Drake, Sara E Hamplova, Ella K Lacey, Perle Roche, Monlan Yuan, Saba S Hazaveh, Eunjung A Lee, David A Bennett, Bruce A Yankner.
      The earliest molecular changes in Alzheimer's disease (AD) are poorly understood1-5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.
    DOI:  https://doi.org/10.1038/s41586-025-09335-x
  23. Nat Commun. 2025 Aug 08. 16(1): 7332
    Regional heterogeneity of the blood-brain barrier.
    Marie Blanchette, Kaja Bajc, Benjamin D Gastfriend, Caterina P Profaci, Nadine Ruderisch, Cayce E Dorrier, Guo Zhong, Raquel Cuevas-Diaz Duran, Sean S Harvey, Iris H Garcia-Pak, Lucija Pintarić, Manon Leclerc, Louise Reveret, Vincent Émond, Annette Wang, Deepti Pant, Linus T Tsai, Frédéric Calon, Nina Isoherranen, Sean P Palecek, Eric V Shusta, Jiaqian Wu, Richard Daneman.
      The blood-brain barrier (BBB), formed by specialized endothelial cells (ECs), regulates the extracellular composition of the central nervous system (CNS). Little is known about whether there are regional specializations of the BBB that may control the function of specific neural circuits. We use single cell RNA-seq to characterize ECs from nine CNS regions in male mice: cortex, hippocampus, cerebellum, spinal cord, striatum, thalamus, hypothalamus, midbrain, and medulla/pons. Although there is a core BBB transcriptional profile, there are significant regional specializations. Stra6, a retinoid transporter, is highly enriched in the BBB of the nucleus accumbens shell (ShNAc) and ventral cochlear nucleus, and is controlled by dietary vitamin A, through endothelial RARƔ. EC Stra6 regulates the deposition of retinoids specifically in the ShNAc and cochlear nucleus, and is required for the function of the ShNAc, in a retinoid-dependent manner. Thus regional specializations of the BBB can regulate the function of local brain regions.
    DOI:  https://doi.org/10.1038/s41467-025-61841-8
  24. Nat Commun. 2025 Aug 04. 16(1): 7158
    Cell surface crowding is a tunable energetic barrier to cell-cell fusion.
    Daniel S W Lee, Liya F Oster, Sungmin Son, Daniel A Fletcher.
      Cell-cell fusion is fundamental to processes such as muscle formation and viral infection. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding reduces fusogenicity independent of how fusion is driven. We estimate that crowding presents an energetic barrier to membrane apposition on the scale of ~ 100kBT , greater than that of bare membrane fusion alone. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease their surface crowding prior to fusion. In this work, we show that cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.
    DOI:  https://doi.org/10.1038/s41467-025-62330-8
  25. Cell. 2025 Jul 29. pii: S0092-8674(25)00798-6. [Epub ahead of print]
    Design of soluble Notch agonists that drive T cell development and boost immunity.
    Rubul Mout, Ran Jing, Mayuri Tanaka-Yano, Emily D Egan, Helen Eisenach, Martin A Kononov, Roland Windisch, Mohamad Ali Toufic Najia, Allison Tompkins, Luca Hensch, Trevor Bingham, Rajesh Gunage, Yunliang Zhao, Natasha I Edman, Christopher Li, Dahai Wang, Thorsten M Schlaeger, Leonard I Zon, Trista E North, Urban Lendahl, R Grant Rowe, David Baker, Stephen C Blacklow, George Q Daley.
      The rational design of receptor agonists to control cell signaling is an emerging strategy for developing disease therapeutics. Creating a soluble cytokine-like agonist for the Notch receptor, which regulates cell fate in embryonic and adult development, is challenging, as receptor activation requires a mechanical force that is usually mediated by cell-associated transmembrane ligands. Here, we exploit computationally designed protein complexes with precise valencies and geometries to generate soluble cytokine-like Notch agonists. These molecules promote cell-cell bridging, cluster Notch receptors at cell synapses, and activate receptor signaling. We show that these agonists drive T cell differentiation from cord blood progenitors and human induced pluripotent stem cells (iPSCs) and in bioreactor production of T cells in liquid suspension. When delivered intravenously in mice, they stimulate cytokine production, expansion of antigen-specific CD4+ T cells, and antibody class switching. These de-novo-designed ligands can be broadly applied to optimize in vitro cell differentiation and advance immunotherapy development.
    Keywords:  Notch signaling; T cell development; T cell immunity; computational protein design; iPSC-derived T cells; immunotherapy; protein agonist; soluble Notch activation; vaccine
    DOI:  https://doi.org/10.1016/j.cell.2025.07.009
  26. Nature. 2025 Aug 04.
    Eating ultra-processed foods could make it harder to lose weight.
    Katie Kavanagh.
      
    Keywords:  Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-02451-8
  27. Nat Neurosci. 2025 Aug;28(8): 1577
    Neurons feed tumors.
    Laura Zelenka.
      
    DOI:  https://doi.org/10.1038/s41593-025-02048-4
  28. Nat Cell Biol. 2025 Aug 04.
    A programmed decline in ribosome levels governs human early neurodevelopment.
    Chunyang Ni, Yudong Wei, Barbara Vona, Dayea Park, Yulei Wei, Daniel A Schmitz, Yi Ding, Masahiro Sakurai, Emily Ballard, Leijie Li, Yan Liu, Ashwani Kumar, Chao Xing, Shenlu Qin, Sangin Kim, Martina Foglizzo, Jianchao Zhao, Hyung-Goo Kim, Cumhur Ekmekci, Ehsan Ghayoor Karimiani, Shima Imannezhad, Fatemeh Eghbal, Reza Shervin Badv, Eva Maria Christina Schwaibold, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Zahra Metanat, Hosein Eslamiyeh, Ebtissal Khouj, Saleh Mohammed Nasser Alhajj, Aziza Chedrawi, Khushnooda Ramzan, Jamil A Hashmi, Majed M Alluqmani, Sulman Basit, Danai Veltra, Nikolaos M Marinakis, Georgios Niotakis, Pelagia Vorgia, Christalena Sofocleous, Hane Lee, Won Chan Jeong, Muhammad Umair, Muhammad Bilal, César Augusto Pinheiro Ferreira Alves, Matthew Sieber, Michael Kruer, Henry Houlden, Fowzan S Alkuraya, Elton Zeqiraj, Roger A Greenberg, Can Cenik, Leqian Yu, Reza Maroofian, Jun Wu, Michael Buszczak.
      Many neurodevelopmental defects are linked to genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remains unclear. Here we describe variants in the ribosome biogenesis factor AIRIM/C1orf109 that are primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic, single-cell RNA sequencing and single-organoid translation analyses, we identify a previously unappreciated drop in protein production during early brain development. We find that ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity suppresses the growth and developmental defects associated with AIRIM/C1orf109 variants. This work provides evidence for the functional importance of regulated changes in global protein synthesis capacity during cellular differentiation.
    DOI:  https://doi.org/10.1038/s41556-025-01708-8
  29. Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00300-6. [Epub ahead of print]37(8): 1630-1632
    Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.
    Eugenio Barone, D Allan Butterfield.
      Insulin resistance is a risk factor for Alzheimer's disease (AD). Chen et al.1 show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.005
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