MIMETAS’ Post

📃Scientific paper: Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential Abstract: Synaptic abnormalities are a cardinal feature of Alzheimer’s disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD. Discover the rest of the scientific article on es/iode ➡️https://etcse.fr/RSQBU #alzheimer #science #health

#ScienceFridays 🔬 Research paper of the week ➡ 'Uncovering neuroinflammation-related modules and potential repurposing drugs for Alzheimer's disease through multi-omics data integrative analysis’ 🔎 Abstract: Neuroinflammation is one of the key factors leading to neuron death and synapse dysfunction in #AlzheimersDisease (AD). Amyloid-β is thought to have an association with microglia activation and trigger neuroinflammation in AD. In this study, researchers present potential repurposing drugs for #Alzheimers, shedding new light on the mechanistic investigation and treatment of the disease. ✍️ Authors: Shensuo Li, Changhao Lu, Zhenzhen Zhao, Dong Lu and  Guangyong Zheng 🏫 Institutions: Shanghai University of Traditional Chinese Medicine and Università degli Studi di Sassari 🔗 Find the link to the article on our #DrugRepurposing Research Collection, curated via ScienceOpen 👇

🚀 Exciting News in ALS Research! 🧬 We are on the brink of a groundbreaking era for Amyotrophic Lateral Sclerosis (ALS) treatment, thanks to recent advancements in antisense oligonucleotides (ASOs) therapy. With the FDA's approval of a novel ASO therapy targeting SOD1 mutations, we are witnessing a pivotal moment in personalized medicine for ALS patients. 🔍 Key Findings: ✅ FDA-Approved Therapy: Downregulating superoxide dismutase 1 (SOD1) with ASOs offers a new treatment avenue for ALS patients with SOD1 mutations. 🧪 Precision Medicine: The success of ASO therapies underscores the importance of understanding the molecular mechanisms of ALS to develop effective treatments. 📊 Individualized Treatment: Patients with rare genetic forms of ALS can benefit from bespoke ASO therapies targeting specific disease-causing genes. 🔄 Restoring Splice Defects: ASOs can counteract TDP-43 nuclear depletion effects, prevalent in most ALS patients, by correcting splice defects in mRNAs. 🌱 Broader Implications: ASOs targeting ALS risk factors or general disease mechanisms may offer new hope for sporadic ALS patients. 📚 A Brief History of ALS & Challenges in Drug Development: ALS, also known as Lou Gehrig's disease, has long been a formidable challenge for the pharmaceutical industry. The complexity of the disease, characterized by the degeneration of motor neurons leading to muscle weakness and eventual paralysis, has made finding effective treatments exceptionally challenging. Historically, the heterogeneity of ALS and the limited understanding of its pathogenesis have posed significant obstacles to drug development. 🔬 The introduction of ASO therapy marks a significant breakthrough, offering a glimmer of hope for personalized and more effective treatments. Yet, the journey to this point underscores the critical need for continued research and innovation. link: https://lnkd.in/gtHjQy4b #ALSResearch #InnovationInMedicine #GeneticTherapy #PersonalizedMedicine #ASOTherapy #FDAApproval #Neuroscience #Biotech

TAMARIN study is top listed in ‘Cancer, Clinical trials' collection, Nature Communication: https://lnkd.in/e3HdJK2g Using a 'benchside to bedside to benchside' approach, the preclinical investigation and clinical trial comprehensively elucidate an insufficiently recognized mechanism of action of selective oestrogen receptor modulators, which could instruct therapeutic approaches in myeloproliferative neoplasms and other haematological malignancies. We sincerely hope TAMARIN study would provide an insightful inspiration for future drug repositioning researches, especially those focusing on hormone therapy. Again, great thanks to all participants of TAMARIN trial, clinical trial team, Mendez-Ferrer group, Professor Claire Harrison and Professor Simón Méndez-Ferrer.  

The result of phase 2 TAMARIN study is available online. This research focuses on the molecular and therapeutic significance of tamoxifen in the myeloproliferative neoplasms (MPN) and provides a novel insight into the metabolic susceptibility of malignant haematopoietic cells. Enormous thanks to the patients and their families for making this study possible. My sincere gratitude to Professor Simón Méndez-Ferrer, Professor Claire Harrison and the whole TAMARIN team. Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis

I want to share with you a pre-print on #bioRxiv of a study I conducted with my valued colleague and friend Tom Boerstler. We investigate the reasons behind the termination of the clinical trial of the #RNA #splicing modulator branaplam in #Huntingtonsdisease. Via thorough data analysis and human in vitro models, we find that branaplam causes nucleolar stress and activation of p53 signaling. In #iPSC derived neurons, this leads to neurite fragmentation and increase of neurofilament light chain levels in the media supernatant, a clinical parameter of neurodegeneration also observed to be elevated in the clinical trial and one reason for its termination. It feels disappointing when promising molecules unexpectedly fail clinical investigations for a devastating disease like Huntington’s disease. However, as a scientist and being in the last steps of becoming a medical doctor, I believe it is crucial to get behind the reasons for such observation since this may help drug design and therefore improve conduction of safe and effective clinical trials using promising therapeutic strategies such as RNA-targeting small molecules. Hope to be sharing a peer-reviewed publication of these findings soon. Thanks to #FAU / University Hospital Erlangen team who helped (Laura Krumm, Stephanie Reischl and Martin Regensburger) and the two senior authors Jürgen Winkler and Beate Winner.

🔬 New Publication Alert! Excited to share our latest research published in Circulation Research! We established a novel human-like murine model of PH that can be broadly used for future mechanistic and translational studies. Our study also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH. https://lnkd.in/gNuyk6bN

📃Scientific paper: Turning the tide on Alzheimer’s disease: modulation of γ-secretase Abstract: Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,” which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be... Discover the rest of the scientific article on es/iode ➡️https://etcse.fr/G5vC #alzheimer #science #health

📃Scientific paper: Turning the tide on Alzheimer’s disease: modulation of γ-secretase Abstract: Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,” which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be... Discover the rest of the scientific article on es/iode ➡️https://etcse.fr/16M4 #alzheimer #science #health