Article
Multidisciplinary Sciences
Xiuhua Yin, Hong Zhou, Mengling Zhang, Juan Su, Xiao Wang, Sijie Li, Zaixing Yang, Zhenhui Kang, Ruhong Zhou
Summary: This study discovered an ultra-small nanodot, C3N, that inhibits the aggregation of A beta peptides and improves behavioral deficits in an AD mouse model. C3N nanodots not only reduce the levels of A beta peptides but also protect neurons and synapses.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Physical
Adolfo B. Poma, Tran Thi Minh Thu, Lam Tang Minh Tri, Hoang Linh Nguyen, Mai Suan Li
Summary: Alzheimer's disease is a neurodegenerative disorder associated with A beta peptide aggregation. Recent experiments suggest that oligomers are more toxic than mature fibrils, leading researchers to investigate factors that may influence the properties of oligomers.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Multidisciplinary Sciences
David Baglietto-Vargas, Stefania Forner, Lena Cai, Alessandra C. Martini, Laura Trujillo-Estrada, Vivek Swarup, Marie Minh Thu Nguyen, Kelly Do Huynh, Dominic Javonillo, Kristine Minh Tran, Jimmy Phan, Shan Jiang, Eniko A. Kramar, Cristina Nunez-Diaz, Gabriela Balderrama-Gutierrez, Franklin Garcia, Jessica Childs, Carlos J. Rodriguez-Ortiz, Juan Antonio Garcia-Leon, Masashi Kitazawa, Mohammad Shahnawaz, Dina P. Matheos, Xinyi Ma, Celia Da Cunha, Ken C. Walls, Rahasson R. Ager, Claudio Soto, Antonia Gutierrez, Ines Moreno-Gonzalez, Ali Mortazavi, Andrea J. Tenner, Grant R. MacGregor, Marcelo Wood, Kim N. Green, Frank M. LaFerla
Summary: The researchers created a mouse model that expresses wildtype human A β, demonstrating effects on cognition, synaptic plasticity, brain changes, inflammation, PAS granules, and gene expression. Furthermore, excision of exon 14 through Cre-mediated methods reduced A β expression and rescued cognitive impairments.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Soha Alali, Gholamhossein Riazi, Mohammad Reza Ashrafi-Kooshk, Sogol Meknatkhah, Shahin Ahmadian, Mohammad Hooshyari Ardakani, Baharak Hosseinkhani
Summary: A hallmark of Alzheimer's disease is the accumulation of tau protein in the brain. CBD may serve as a potent substance to hinder tau aggregation in AD. Studies using biochemical methods have shown that CBD can suppress tau fibrils formation.
Article
Multidisciplinary Sciences
Dongtak Lee, Dongsung Park, Insu Kim, Sang Won Lee, Wonseok Lee, Kyo Seon Hwang, Jeong Hoon Lee, Gyudo Lee, Dae Sung Yoon
Summary: The study demonstrates the creation of an amyloid corona around a plasmonic nanoparticle for monitoring the degradation of amyloid when exposed to potential drugs, offering an appealing opportunity to reduce attrition problems in drug discovery for AD treatment.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Zhongju Ye, Zhao-Jun Yan, Chenhong Zhang, Jun-Li Hou, Shijing Yue, Lehui Xiao
Summary: Anti-A beta therapy has been the main focus in clinical trials for AD prevention and treatment. This study introduced a new strategy using a charged tubular supramolecule to suppress A beta fibrillation, showing efficient inhibition of A beta(40) fibrillation by CTS-A at a very low inhibitor:peptide molar ratio (1:10) and a reduced cytotoxic effect of A beta peptides post-inhibition or disaggregation. The organized supramolecular structure enhances amyloid fibrillar modulation, offering a new approach for AD treatment using supramolecules.
Review
Biochemistry & Molecular Biology
Kseniya B. Varshavskaya, Vladimir A. Mitkevich, Alexander A. Makarov, Evgeny P. Barykin
Summary: This article compares the structure and biological effects of different sources of Aβ preparations, discusses their applicability in AD modeling, and explores the reasons for the differences in effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Juliana Rey, Maike Breiden, Vanda Lux, Anika Bluemke, Maike Steindel, Kamilla Ripkens, Bastian Moellers, Kenny Bravo Rodriguez, Prisca Boisguerin, Rudolf Volkmer, Joel Mieres-Perez, Tim Clausen, Elsa Sanchez-Garcia, Michael Ehrmann
Summary: This study reports a novel and reversible mechanism of protease activation, where an inactive protease serves as the activator. This mechanism involves the formation of an allosteric complex between HTRA1 and calpain 2, and exhibits activity only towards specific conformations of substrates. These findings have important implications for understanding protein quality control and potential side effects of drug modulation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Aruna K. Mora, Sushant Murudkar, Neelam Shivran, Soumyaditya Mula, Subrata Chattopadhyay, Sukhendu Nath
Summary: Protein oligomers, formed under physiological stress, are neurotoxic and linked to neurological diseases. Early detection is crucial, and a new NIR-emitting fluorescent probe has been developed for this purpose. The probe not only detects matured fibrils but also probes oligomer formation, showing potential for in vivo imaging.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Review
Biochemistry & Molecular Biology
Yuanxin Zhao, Buhan Liu, Jian Wang, Long Xu, Sihang Yu, Jiaying Fu, Xiaoyu Yan, Jing Su
Summary: Neuroinflammation mediated by microglia is a common feature in neurodegenerative diseases. The accumulation of Aβ and tau proteins can disrupt the metabolism of microglia, leading to neuroinflammation.
Article
Biochemistry & Molecular Biology
Addison Frese, Cody Goode, Kiryl Zhaliazka, Aidan P. Holman, Tianyi Dou, Dmitry Kurouski
Summary: The aggregation of misfolded proteins is the fundamental molecular cause of severe pathologies such as Alzheimer's and Parkinson's diseases. Lipids are found to play a vital role in this process. In this study, the researchers investigated the impact of the length and saturation of fatty acids in phosphatidylserine (PS) on lysozyme aggregation. The results showed that both factors influenced the aggregation rate of insulin. The presence of double bonds in fatty acids accelerated the rate of insulin aggregation relative to PS with fully saturated fatty acids.
Article
Neurosciences
Meiting Li, Nan Cai, Liang Gu, Lijun Yao, Decheng Bi, Weishan Fang, Zhijian Lin, Yan Wu, Hong Xu, Hui Li, Zhangli Hu, Xu Xu
Summary: Genipin shows promising effects on inhibiting Tau aggregation and Aβ generation through multiple molecular mechanisms, making it a potential therapeutic agent or nutraceutical for Alzheimer's disease.
MOLECULAR NEUROBIOLOGY
(2021)
Article
Neurosciences
Jiang Wu, Jijun Xu, Mohamed Naguib, Bihua Bie
Summary: This study found that dysfunction of type 2A PPase signaling contributes to complement C1q-dependent microglial phagocytosis of glutamatergic synapses and cognitive impairments in a rat model of Alzheimer's disease.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Parvin Babaei
Summary: Alzheimer's disease is characterized by cognitive dysfunction and synaptic failure, with neurodegeneration negatively correlated with synaptic plasticity. Glutamatergic neurotransmission via NMDA and AMPA receptors is critical for synaptic plasticity, but excessive glutamate concentration can lead to excitotoxicity and neurodegeneration. Imbalances in NMDA and AMPA receptors can cause synaptopathy in AD.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ada De Luigi, Laura Colombo, Luca Russo, Caterina Ricci, Antonio Bastone, Sara Cimini, Fabrizio Tagliavini, Giacomina Rossi, Laura Cantu, Elena Del Favero, Mario Salmona
Summary: Understanding the pathogenetic mechanisms in tauopathy-associated neurodegenerative diseases can be improved by studying the biochemical and biophysical features of mutated tau proteins. This study compared the behavior of wild-type and mutated tau proteins using various techniques, and found that there is diversity in their recruitment kinetics and aggregate structures throughout the process. The different extent of conformational changes and types of molecular assemblies among the proteins also reflected in their in vitro toxicity.
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
(2022)
Article
Biology
Ryan Limbocker, Benedetta Mannini, Francesco S. Ruggeri, Roberta Cascella, Catherine K. Xu, Michele Perni, Sean Chia, Serene W. Chen, Johnny Habchi, Alessandra Bigi, Ryan P. Kreiser, Aidan K. Wright, J. Alex Albright, Tadas Kartanas, Janet R. Kumita, Nunilo Cremades, Michael Zasloff, Cristina Cecchi, Tuomas P. J. Knowles, Fabrizio Chiti, Michele Vendruscolo, Christopher M. Dobson
COMMUNICATIONS BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Elham Rezvani Boroujeni, Seyed Masoud Hosseini, Giulia Fani, Cristina Cecchi, Fabrizio Chiti
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Clinical Neurology
Alessandra Bigi, Gilda Loffredo, Roberta Cascella, Cristina Cecchi
CURRENT ALZHEIMER RESEARCH
(2020)
Article
Biochemistry & Molecular Biology
Giulia Fani, Benedetta Mannini, Giulia Vecchi, Roberta Cascella, Cristina Cecchi, Christopher M. Dobson, Michele Vendruscolo, Fabrizio Chiti
Summary: Alzheimer's disease, the most common form of dementia, is characterized by the toxicity mechanism of Aβ oligomers through perturbing the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Biology
Alessandra Bigi, Emilio Ermini, Serene W. Chen, Roberta Cascella, Cristina Cecchi
Summary: This study found that prefibrillar oligomers of alpha-synuclein can quickly penetrate neuronal membranes, leading to cell dysfunction; on the other hand, fibril docking to the phospholipid bilayer causes conformational changes in alpha-synuclein, releasing harmful oligomers.
Review
Biochemistry & Molecular Biology
Roberta Cascella, Alessandra Bigi, Nunilo Cremades, Cristina Cecchi
Summary: Protein misfolding is a common feature of protein deposition diseases, and soluble oligomeric species may be more toxic than fibrillar forms. Recent research shows that the beta-sheet core of aSyn fibrils cannot establish persistent interactions with lipid bilayers, but can release oligomeric species that cause immediate dysfunction. These oligomeric species can also contribute to pathogenesis through neuron-to-neuron spreading.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Multidisciplinary Sciences
Roberta Cascella, Alessandra Bigi, Dylan Giorgino Riffert, Maria Cristina Gagliani, Emilio Ermini, Matteo Moretti, Katia Cortese, Cristina Cecchi, Fabrizio Chiti
Summary: This study used high-resolution microscopy to monitor the formation of TDP-43 aggregates in neurons and found that neuronal dysfunction in neurodegenerative diseases is associated with the formation of large cytoplasmic inclusions. Unlike other diseases, the toxicity in these diseases is attributed to large aggregates rather than small oligomers. The proteasome and autophagy target the largest deleterious inclusions, but their efficiency decreases over time.
Review
Biochemistry & Molecular Biology
Alessandra Bigi, Roberta Cascella, Fabrizio Chiti, Cristina Cecchi
Summary: Amyloid fibril formation and the release of oligomers cause sustained damage to neurons and glial cells, and enable diffusion between cells.
Article
Medicine, General & Internal
Roberta Cascella, Martina Banchelli, Seyyed Abolghasem Ghadami, Diletta Ami, Maria Cristina Gagliani, Alessandra Bigi, Tommaso Staderini, Davide Tampellini, Katia Cortese, Cristina Cecchi, Antonino Natalello, Hadi Adibi, Paolo Matteini, Fabrizio Chiti
Summary: This study investigated the morphological, structural, and tinctorial properties of TAR DNA-binding protein 43 (TDP-43) inclusions in neuroblastoma x spinal cord 34 (NSC-34) cells. The results showed that TDP-43 inclusions did not exhibit amyloid properties and lacked cross-beta structure and fibrillar morphology. These findings suggest that TDP-43 has a low propensity to form amyloid fibrils and instead forms other types of inclusions.
ANNALS OF MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Tommaso Staderini, Alessandra Bigi, Daniele Mongiello, Cristina Cecchi, Fabrizio Chiti
Summary: Amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions are associated with deposition of cytosolic inclusion bodies of TAR DNA-binding protein 43 (TDP-43) in brain and motor neurons. We induced phase separation of purified full-length TDP-43 devoid of large tags using a solution-jump method, and monitored it with an array of biophysical techniques. The tetramethylrhodamine-5-maleimide- or Alexa488-labeled protein formed rapidly (<1 min) apparently round, homogeneous and 0.5-1.0 mu m wide assemblies, when imaged using confocal fluorescence, bright-field, and stimulated emission depletion microscopy. The assemblies, however, had limited internal diffusion, as assessed with fluorescence recovery after photobleaching, and did not coalesce, but rather clustered into irregular bunches, unlike those formed by the C-terminal domain. They were enriched with alpha-helical structure, with minor contributions of beta-sheet/random structure, had a red-shifted tryptophan fluorescence and did not bind thioflavin T. By monitoring with turbidimetry both the formation of the spherical species and their further clustering under different experimental conditions, we carried out a multiparametric analysis of the two phenomena. In particular, both processes were found to be promoted by high protein concentrations, salts, crowding agents, weakly by reducing agents, as the pH approached a value of 6.0 from either side (corresponding to the TDP-43 isoionic point), and as the temperature approached a value of 31 degrees C from either side. Important differences were found with respect to the TDP-43 C-terminal domain. Our multiparametric results also provide explanations to some of the solubility data obtained on full-length TDP-43 that were difficult to explain following the multiparametric analysis acquired on the C-terminal domain.
Editorial Material
Biochemistry & Molecular Biology
Alessandra Bigi, Eva Lombardo, Roberta Cascella, Cristina Cecchi
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Silvia Errico, Giacomo Lucchesi, Davide Odino, Enass Youssef Osman, Roberta Cascella, Lorenzo Neri, Claudia Capitini, Martino Calamai, Francesco Bemporad, Cristina Cecchi, William A. Kinney, Denise Barbut, Annalisa Relini, Claudio Canale, Gabriella Caminati, Ryan Limbocker, Michele Vendruscolo, Michael Zasloff, Fabrizio Chiti
Summary: Natural aminosterols are potential drugs for treating neurodegenerative diseases, and their protective mechanism involves binding to biological membranes and inhibiting amyloidogenic proteins. Three chemically different aminosterols were compared and found to have different binding affinities, charge neutralizations, mechanical reinforcements, and lipid redistributions within liposomes. They also exhibited varying potency in protecting cell membranes against amyloid-beta oligomers. Overall analysis provided an analytical equation that quantitatively described the protective effects of aminosterols based on their concentration and membrane effects, linking their chemistry to membrane protection.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)