Review
Chemistry, Multidisciplinary
John H. Viles
Summary: The accumulation of amyloid-beta peptides (Aβ) is crucial in Alzheimer's disease development. The interaction between various Aβ assemblies and lipid membranes or membrane receptors result in increased membrane permeability and cellular homeostasis disruption, which plays a key role in the pathology of Alzheimer's disease. Aβ can affect lipid membranes in multiple ways, including a carpeting effect, a detergent effect, and the formation of Aβ ion-channel pores. Recent advancements in imaging techniques have improved our understanding of Aβ-induced membrane disruption. Understanding the relationship between different Aβ structures and membrane permeability will guide the development of therapeutics targeting Aβ cytotoxicity.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Neurosciences
Fadi Rofo, Jos Buijs, Ronny Falk, Ken Honek, Lars Lannfelt, Anna M. Lilja, Nicole G. Metzendorf, Tobias Gustavsson, Dag Sehlin, Linda Soderberg, Greta Hultqvist
Summary: A new antibody design with increased valency was developed to enhance binding avidity to a wider range of sizes of A beta aggregates. Real-time interaction analysis and ELISA experiments demonstrated the successful binding to A beta protofibrils and small oligomers, while showing protective effects against A beta-induced cell death.
TRANSLATIONAL NEURODEGENERATION
(2021)
Article
Clinical Neurology
Shobha Dhadda, Michio Kanekiyo, David Li, Chad J. Swanson, Michael Irizarry, Scott Berry, Lynn D. Kramer, Donald A. Berry
Summary: The sensitivity analysis demonstrates that Lecanemab shows positive effects in treating Alzheimer's disease across different statistical methods, endpoints, and over time.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Kapur B. Dhami, Sanjib Karki, Antanisha Parks, Cameron G. Nichols, Michael R. Nichols
Summary: Three decades of research have shown the conformational heterogeneity of amyloid β peptide (Aβ) in Alzheimer's disease (AD). The differences in conformation between Aβ species are still not fully understood, but they provide insights into protein misfolding and aggregation. In this study, different strategies were used to separate Aβ protofibrils and oligomers, and it was found that the smaller Aβ oligomers have a different conformation than Aβ protofibrils.
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
(2022)
Article
Biochemistry & Molecular Biology
Erica Caballero, Elena Hernando-Perez, Victor Tapias, Maria Calvo-Rodriguez, Carlos Villalobos, Lucia Nunez
Summary: The Aβ oligomers in Alzheimer's disease promote calcium influx by amyloid channels and NMDA receptors, leading to excitotoxicity and neuron degeneration.
Article
Biochemistry & Molecular Biology
Meenakshi Pillai, Santosh Kumar Jha
Summary: TDP-43 protein is associated with neurodegenerative diseases and can adopt different oligomeric and fibrillar states. However, the kinetic understanding of its structural transformation is still lacking. This study reveals that aggregation of TDP-43 occurs in four distinct steps, involving conformational conversion, oligomerization, and formation of higher order intermediates (HOI), before ultimately forming an amyloid-like assembly. The formation of ThT binding sites and conformational conversion depends on the protein concentration. The aggregation process follows a linear polymerization reaction without a lag phase.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Article
Biochemistry & Molecular Biology
Qize Xuan, Jiaxin He, Wenxue Zhang, Wei Zhang, Qi Zhang, Yao Zhou, Anqi Wei, Hao Wang, Hui Li, Chao Chen, Ping Wang
Summary: This study successfully prepared three different morphological and structural phenol-soluble modulin alpha 3 (PSM alpha 3) assemblies using the strategy of salt-inducing assembly polymorphism. It was found that amyloid fibrillation was essential for enhancing the cytotoxicity of PSM alpha 3, and the size and structure of PSM alpha 3 fibrils played a crucial role in cytotoxicity. The cytotoxicity was achieved through a membrane-disrupting mechanism, with different fibril types causing membrane thinning or perforation.
Review
Chemistry, Multidisciplinary
Ryan Limbocker, Nunilo Cremades, Roberta Cascella, Peter M. Tessier, Michele Vendruscolo, Fabrizio Chiti
Summary: The misfolding and aggregation of peptides and proteins into amyloid aggregates is a common feature of various protein misfolding diseases, including Alzheimer's disease and Parkinson's disease. Misfolded protein oligomers, which can form intermediates in the fibril formation process or be released by mature fibrils, are increasingly recognized as central to the development of these diseases. Despite challenges in studying these oligomers, researchers have developed methods to produce stable and reproducible populations for experimentation. These tools have provided insights into the structural determinants of oligomer toxicity and potential therapeutic strategies.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Li Wang, Kilho Eom, Taeyun Kwon
Summary: The study found that in the initial stage of aggregation process for both Aβ40 and Aβ42, multiple particles are formed which later self-assemble to form amyloid fibrils of different shapes. Different aggregation pathways of Aβ isoforms lead to amyloid fibrils with contrasting structures.
Article
Biochemistry & Molecular Biology
Biao Xiao, Chao-Yang Chu, Jiang-Hui Shan, Qing-Juan Wang, Wei Shen, Kai Xie, Li-ping Li
Summary: Alzheimer's disease (AD) is a neurodegenerative disease with severe cognitive disorder, particularly prevalent in the elderly population. Currently, there are no specific drugs for AD, and the clinical drugs available only alleviate symptoms without halting or reversing disease progression. The formation of amyloid P (AP) is a key pathological feature in AD, but therapies targeting AP have shown limited success in clinical trials, highlighting the need for more rigorous experimental design and reexamination of AP's role in the disease.
PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Multidisciplinary Sciences
Jaekyun Jeon, Wai-Ming Yau, Robert Tycko
Summary: The self-assembly process of amyloid-beta peptides in Alzheimer's disease was studied using time-resolved solid-state NMR and light scattering experiments. Results showed that within one millisecond, beta-strand conformations and intermolecular contacts between different segments of amyloid-beta molecules started to form. These findings suggest that the initial structures of oligomers are different from those of protofibrils and fibrils.
NATURE COMMUNICATIONS
(2023)
Review
Virology
Wesley R. Naeimi, Tricia R. Serio
Summary: The formation of amyloid fibers is associated with various diseases and phenotypic conditions, and they can assemble into multi-protofibril and high-order architectures. Using prion propagation in yeast as a model, researchers can explore the connection between these aggregation states and the biological consequences of amyloid dynamics.
Article
Mathematics, Applied
P. Ghosh, J. Pateras, V Rangachari, A. Vaidya
Summary: The self-assembly of proteins into amyloid aggregates is important in neurodegenerative diseases, with a focus on understanding the formation and behavior of toxic oligomers. A theoretical framework is expanded to explore the network topological structures in amyloid formation kinetics. The use of thermodynamic free energy computations and mechanistic approaches help identify dominant pathways and intervention strategies to draw dynamics away from off-pathways.
APPLIED MATHEMATICS AND COMPUTATION
(2021)
Article
Chemistry, Multidisciplinary
Zhengxin Yu, Weijie Guo, Shrey Patel, Hong-Jun Cho, Liang Sun, Liviu M. Mirica
Summary: This study developed twelve small molecule compounds with different amphiphilic properties, which showed high binding affinity to the hallmark Aβ plaques and oligomers of Alzheimer's disease. These compounds also exhibited the ability to alleviate Cu2+-Aβ induced toxicity and disrupt the interactions between Aβ oligomers and cell membranes.
Article
Biochemistry & Molecular Biology
Stewart R. Durell, Rakez Kayed, H. Robert Guy
Summary: Amyloid beta (A beta) peptides, particularly A beta 42, contribute to Alzheimer's disease. Molecular models of A beta 42 hexamers have been proposed, and experimental findings support various aspects of these models. Recent studies have also proposed structures for A beta 42 tetramers and octamers. Differing assembly types for A beta 42 have been identified, and concentric beta-barrel models have been proposed.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2022)
Article
Biochemistry & Molecular Biology
Santosh Kumar, Sumati Rajagopalan, Pabak Sarkar, David W. Dorward, Mary E. Peterson, Hsien-Shun Liao, Christelle Guillermier, Matthew L. Steinhauser, Steven S. Vogel, Eric O. Long
Review
Immunology
Santosh Kumar
Article
Biochemistry & Molecular Biology
Santosh Kumar, Jayant B. Udgaonkar
Review
Immunology
Santosh Kumar, Shweta Jain
Article
Immunology
Santosh Kumar, Pabak Sarkar, Malcolm J. W. Sim, Sumati Rajagopalan, Steven S. Vogel, Eric O. Long
JOURNAL OF IMMUNOLOGY
(2015)
Article
Multidisciplinary Sciences
Sitanshu Kumar Sarangi, Kashmiri M. Lande, Santosh Kumar
Summary: Many receptors signal through phosphorylation of tyrosine-based motifs in their cytosolic tails, which have intrinsic disorder as a common feature. This study focuses on the polyampholytic disordered region of the cytosolic tails of inhibitory receptors, which have acidic and basic residues linearly segregated. The electrostatic interactions between these residues and the membrane lipids regulate the phosphorylation and signaling of the receptors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Meeting Abstract
Biophysics
Santosh Kumar
BIOPHYSICAL JOURNAL
(2023)
Review
Multidisciplinary Sciences
Santosh Kumar, Jayant B. Udgaonkar
Article
Biochemistry & Molecular Biology
Santosh Kumar, Subhendu K. Mohanty, Jayant B. Udgaonkar
JOURNAL OF MOLECULAR BIOLOGY
(2007)
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)