Alexander Dömling’s Post

Unlocking CNS RNA-based therapeutics using ionizable nanoemulsions: scientific curiosity or real clinical potential? The use of LNPs for targeting complex tissues like the central nervous system remains limited due to poor diffusivity and challenges in overcoming brain barriers. Addressing this critical bottleneck, a quite recent research introduces a "potentially transformative" solution: ionizable nanoemulsions (or iNEs), designed to enhance the delivery and efficacy of RNA-based genetic therapeutics within the CNS. The newly developed iNEs are engineered with a unique combination of C12–200, DOPE, Vitamin E, and DMG-PEG, achieving a formulation that is not only potent but also physiologically compatible. With a particle size under 100 nm and a neutral surface charge, these nanoemulsions exhibited a high RNA loading capacity. Furthermore, the iNEs demonstrated excellent cell viability and transfection efficiency across several cellular models, including neurons, astrocytes, and microglia—key components of the CNS. In a pivotal set of experiments, iNEs loaded with mRNA encoding GFP were administered intra-parenchymally to test their CNS transfection capabilities. The results were striking: the iNEs not only diffused effectively within the brain's complex tissue architecture but also selectively transfected neurons, showcasing their potential to bypass the stringent barriers that typically impede genetic delivery to the brain. By enhancing the diffusivity and targeting capabilities of RNA carriers, ionizable nanoemulsions potentially open new avenues for the treatment of neurological disorders, offering hope for therapies that require precise genetic modifications at the cellular level. Learn more here: https://lnkd.in/eqrcp7vP #Neuroscience #GeneticTherapy #Nanotechnology #Biotechnology #RNAtherapy #InnovativeResearch #DrugDelivery #CNS #BrainHealth #ScientificBreakthrough

Therapeutic Potential of Schwann Cell-Derived Exosomes in Mitochondrial Dysfunction & Necroptosis After Spinal Cord Injury! Xu et al. from the Tongji University School of Medicine in China introduced a promising approach to address the impacts of spinal cord injury (SCI). They explored the efficacy of Schwann cell-derived exosomes (SCDEs) in mitigating mitochondrial dysfunction, a key aspect of SCI pathology. Key finding of the study: SCDEs reduce oxidative stress, inflammation, and necroptosis post-SCI. In vitro experiments show SCDEs enhance mitophagy, improving mitochondrial function. SCDEs induce mitophagy via the AMPK signaling pathway. This research highlights SCDEs as a potential therapeutic strategy for SCI, offering new insights into mitigating cellular damage and improving outcomes. 🔗 Read more: https://lnkd.in/dKmcYj-V Join us in Malta this October for the First World Congress on Targeting Extracellular Vesicles to learn more about the potential of exosomes in treating mitochondrial dysfunctions! 🌐 Conference Website: https://lnkd.in/dMm8jZjd #TargetingExtracellularVesicles #TargetingEVs #evs #exosomes #exosome #redox #mitochondria #mitochondrialdisease #schwamcells  #ISM #WMS

Our latest study is published in the Translational Stroke Research. We investigated how SARS-CoV-2 spike protein exacerbates stroke and cerebrovascular complications. Our study showed that SARS-CoV2 increases coagulation and decreases fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS) in the brain. Thanks to my research team for the hard work. I am always proud of your work. https://lnkd.in/eHM78CE3 Heath SP, Hermanns VC, Coucha M, Abdelsaid M. SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model. Transl Stroke Res. 2024 Oct 2. doi: 10.1007/s12975-024-01301-5. Epub ahead of print. PMID: 39354270.

Thrilled to announce our latest publication on plasma NTA-tau! This #immunoassay is the first #blood method specifically reflecting in vivo #tau pathology in #Alzheimer’s disease (AD). This innovative #biomarker holds promise as a cost-effective and accessible tool for tracking disease progression and cognitive decline in clinical settings. Moreover, it may serve as a valuable outcome measure in clinical trials, particularly those assessing the downstream effects of Aβ removal. Key highlights: - Plasma NTA-tau increases across the AD continuum, especially during mid-to-late AD stages. - In Aβ positive participants, plasma NTA-tau strongly associates with tau #PET, cortical thickness (#MRI), and cognition. - Baseline plasma NTA-tau levels predict longitudinal tau accumulation, atrophy, and cognitive decline. - Longitudinal changes in plasma NTA-tau associate with Aβ pathology status in asymptomatic and symptomatic participants. - Longitudinal changes in plasma NTA-tau associate with over time changes in brain atrophy and cognition. Fantastic collaboration between University of Gothenburg, and Lund University. Big congrats to Gemma Salvadó Blasco (joined first author), Anniina Snellman, Laia Montoliu Gaya, Andréa Lessa Benedet, Nicholas Ashton, Wagner Brum, Henrik Zetterberg, Kaj Blennow, Oskar Hansson, and all other authors and collaborators!

Check out our latest review by Prof. Igor Iezhitsa, Prof. Renu Agarwal, and Prof. Puneet Agarwal, "Unveiling the Enigmatic Essence of Sphingolipids: A Promising Avenue for Glaucoma Treatment." Discover how sphingolipids—once shrouded in mystery—are now at the forefront of glaucoma research. Our review highlights the crucial role of sphingolipids in retinal ganglion cell survival and examines innovative therapeutic strategies for retinal neuroprotection. This review paper is a part of the special issue "Glaucoma – Genes and Mechanisms" in Vision Research. 🔗 Read the Full Paper: https://lnkd.in/gapuzy3V #GlaucomaResearch #Sphingolipids #Neuroprotection #OcularPharmacology #Elsevier

Fascinating results from a new phase 1 clinical trial suggest that stem cells derived from patients’ own fat may safely enhance sensation and movement in individuals with traumatic spinal cord injuries. In the study, seven out of ten adults showed measurable improvements on the ASIA Impairment Scale, experiencing increased sensation, muscle strength, and improved bowel function without serious side effects. In the multidisciplinary trial, participants had spinal cord injuries from vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65. Participants’ stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients’ lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times. The results of this early research offer insights into the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited. https://lnkd.in/e5VnNM7N Sources: Neuroscience News, Nature Communications #stemcells #MSC #spinalinjury

🧠 Exciting Research Update!🧠 Are you interested about the potential of combining advanced imaging with metabolic and molecular analyses to further the understanding of AD progression? In our latest work, our team has uncovered how different brain regions are affected by AD over time using a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate pathological interactions in the 5xFAD mouse model of AD. Key findings include: - 🔬Age and region-specific changes in AD markers. - ⚡️Selective disruptions in energy metabolism in the hippocampus and cortex. - 🧠Adaptive responses in brain cells to inflammation. These insights highlight the importance of targeting specific metabolic disturbances in AD treatment. If you want to read more about our findings in these excellent collaborative work between the groups of Associate Professor Kristi A. Kohlmeier, Professor Brian Hansen from Aarhus University and our #NeuroMet group from Dept. of Drug Design and Pharmacology (ILF), University of Copenhagen click here: https://lnkd.in/dgm5qAkJ Emil Westi Saba Molhemi Caroline Termøhlen Aisha Ameen

I am thrilled to announce my co-authorship of the article: "Comprehensive Analysis of the 5xFAD Mouse Model of Alzheimer's Disease Using dMRI, Immunohistochemistry, and Neuronal, and Glial Functional Metabolic Mapping," which has been published in the journal Biomolecules.

📃Scientific paper: Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) have remained largely uncharacterized. We report that selective loss of Tsc1, a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced Aβ clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1-deficient microglia with fluorescent-labeled Aβ revealed enhanced Aβ uptake and clearance, which was blunted by rapamycin, an mTOR inhibitor. In vivo treatment of mice of relevant genotypes in the 5XFAD background with rapamycin, affected microglial activity, decreased Trem2 expression and reduced Aβ clearance causing an increase in Aβ plaque burden. Prolonged treatment with rapamycin caused even further reduction of mTOR activity, reduction in Trem2 expression, and increase in Aβ levels. ... Continued on ES/IODE ➡️ https://etcse.fr/nSf ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you. #alzheimer #science #health

📃Scientific paper: Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) have remained largely uncharacterized. We report that selective loss of Tsc1, a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced Aβ clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1-deficient microglia with fluorescent-labeled Aβ revealed enhanced Aβ uptake and clearance, which was blunted by rapamycin, an mTOR inhibitor. In vivo treatment of mice of relevant genotypes in the 5XFAD background with rapamycin, affected microglial activity, decreased Trem2 expression and reduced Aβ clearance causing an increase in Aβ plaque burden. Prolonged treatment with rapamycin caused even further reduction of mTOR activity, reduction in Trem2 expression, and increase in Aβ levels. ... Continued on ES/IODE ➡️ https://etcse.fr/nSf ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you. #alzheimer #science #health