Article
Biochemistry & Molecular Biology
A. Rai, O. A. Ojiakor, R. J. Rylett
Summary: The ApoE4 allele is a genetic risk factor for Alzheimer's disease, increasing the risk of developing the disease by up to three-fold. This study shows that ApoE4 influences multiple genetic and molecular pathways including neural cell maintenance, insulin signaling, amyloid processing and clearance, and synaptic plasticity. Additionally, ApoE4-expressing mice fed a high-fat diet exhibit metabolic disturbances that are associated with an increased risk of Alzheimer's disease in humans.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Fadi Rofo, Friederike A. Sandbaumhuter, Aikaterini Chourlia, Nicole G. Metzendorf, Jamie Morrison, Stina Syvanen, Per E. Andren, Erik T. Jansson, Greta Hultqvist
Summary: SST-scFv8D3 increases neprilysin activity and promotes the degradation of membrane-bound Aβ42 in Alzheimer's disease, while also regulating mitochondrial function and neurogenesis in the hippocampus of mice.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Neurosciences
Raquel Sanchez-Varo, Elisabeth Sanchez-Mejias, Juan Jose Fernandez-Valenzuela, Vanessa De Castro, Marina Mejias-Ortega, Angela Gomez-Arboledas, Sebastian Jimenez, Maria Virtudes Sanchez-Mico, Laura Trujillo-Estrada, Ines Moreno-Gonzalez, David Baglietto-Vargas, Marisa Vizuete, Jose Carlos Davila, Javier Vitorica, Antonia Gutierrez
Summary: Alzheimer's disease is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. Synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease.
FRONTIERS IN NEUROSCIENCE
(2021)
Editorial Material
Neurosciences
Livia La Barbera, Marcello D'Amelio
Summary: Recent studies have shown the significant influence of sex on the pathophysiology of AD, with worse alterations observed in female mice in terms of amyloid-beta plaque deposition, behavior, and dopaminergic signaling. Therefore, recognizing sex as a key variable is crucial for precise clinical practice and developing sex-specific therapeutic interventions.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Article
Multidisciplinary Sciences
Qing Dong, Louis J. Ptacek, Ying-Hui Fu
Summary: Sleep is important for well-being, and chronic sleep deprivation has negative health consequences. Two familial natural short sleep (FNSS) mutations, DEC2-P384R and Npsr1-Y206H, modify tauopathy in PS19 mice. This study investigated the effect of another FNSS gene variant, Adrb1-A187V, on tau pathology in PS19 mice. The Adrb1-A187V mutation improved REM sleep and reduced tau aggregation in the locus coeruleus (LC) in PS19 mice. ADRB1+ neurons in the central amygdala (CeA) projected to the LC, and stimulating CeAADRB1+ neuronal activity increased REM sleep. Additionally, the Adrb1 mutation attenuated tau spreading from the CeA to the LC, suggesting that it protects against tauopathy by reducing tau accumulation and propagation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Neurosciences
Joakim Bastrup, Kathrine H. Hansen, Thomas B. G. Poulsen, Kenneth Kastaniegaard, Ayodeji A. Asuni, Soren Christensen, Dorthe Belling, Lone Helboe, Allan Stensballe, Christiane Volbracht
Summary: Chronic treatment with aducanumab significantly reduces the number of senile plaques in AD mouse model and alters the proteomic profile of surrounding tissue, potentially inhibiting Aβ toxicity and increase cell viability.
JOURNAL OF ALZHEIMERS DISEASE
(2021)
Article
Multidisciplinary Sciences
Sivaprakasam R. Saroja, Kirill Gorbachev, T. C. W. Julia, Alison M. Goate, Ana C. Pereira
Summary: A protein called glypican-4 (GPC-4) secreted by astrocytes is shown to drive tau hyperphosphorylation induced by APOE4, a genetic risk factor for Alzheimer's disease. This discovery provides insights into the mechanisms underlying tauopathies and highlights the role of GPC-4 in tau accumulation and propagation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Clinical Neurology
Hee Yang Lee, Soljee Yoon, Jeong Hwa Lee, Keunwan Park, Youngeun Jung, Illhwan Cho, Donghee Lee, Jisu Shin, Kyeonghwan Kim, Sunmi Kim, Jimin Kim, Koeun Kim, Seung Hoon Han, Seong Muk Kim, Hye Ju Kim, Hye Yun Kim, Ikyon Kim, Young Soo Kim
Summary: The study identified YIAD002 as a potent dissociator of Aβ aggregates, showing significant reduction in amyloid burden, improved cognitive performance, and alleviated major pathological hallmarks of AD. Mechanism studies suggest that YIAD002 interferes with intermolecular beta-sheet fibrillation by directly interacting with specific domains of Aβ.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Multidisciplinary Sciences
Zihui Li, Daniel M. Tremmel, Fengfei Ma, Qinying Yu, Min Ma, Daniel G. Delafield, Yatao Shi, Bin Wang, Samantha A. Mitchell, Austin K. Feeney, Vansh S. Jain, Sara Dutton Sackett, Jon S. Odorico, Lingjun Li
Summary: This study used mass spectrometry to analyze the ECM proteome of the human pancreas at different age stages, identifying new matrisome features and visualizing specific ECM proteins of interest through immunofluorescent staining. The research contributes to a better understanding of the critical roles that ECM plays throughout human pancreas development and maturation.
NATURE COMMUNICATIONS
(2021)
Article
Clinical Neurology
Shang Wang, Taiyang Zhu, Wanyan Ni, Chao Zhou, Hui Zhou, Li Lin, Yuting Hu, Xiaoyu Sun, Jingjing Han, Yan Zhou, Guoliang Jin, Jie Zu, Hongjuan Shi, Xingxing Yang, Zuohui Zhang, Fang Hua
Summary: This study investigates the role of early activation of Toll-like receptor 3 (TLR3) in the pathophysiological process of Alzheimer's disease (AD). The results showed that the early activation of TLR3 attenuated neuronal loss and neurobehavioral dysfunction in a mouse model of AD. This could be attributed to its role in A beta clearance, the inhibition of glial cells, and the regulation of neuroinflammation in the hippocampus.
ALZHEIMERS RESEARCH & THERAPY
(2023)
Article
Clinical Neurology
Christoph Gericke, Tunahan Kirabali, Roman Flury, Anna Mallone, Chiara Rickenbach, Luka Kulic, Vinko Tosevski, Christoph Hock, Roger M. Nitsch, Valerie Treyer, Maria Teresa Ferretti, Anton Gietl
Summary: This study uses multidimensional mass-cytometry and machine-learning techniques to analyze peripheral blood mononuclear cells. The results show that increases in adaptive immune cells are associated with early accumulation of brain beta-amyloid and changes in plasma AD biomarkers, suggesting a link between preclinical AD pathology and alterations in the adaptive immune system.
ALZHEIMERS & DEMENTIA
(2023)
Article
Biochemistry & Molecular Biology
Mar Cuadrado-Tejedor, Marta Perez-Gonzalez, Rocio Alfaro-Ruiz, Sara Badesso, Diego Sucunza, Maria Espelosin, Susana Ursua, Mercedes Lachen-Montes, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Rafael Lujan, Ana Garcia-Osta
Summary: The study found that overexpression of hTauP301L in APP/PS1 transgenic mice accelerates memory deficits and induces tau aggregation, but does not affect memory function in wild type mice. The presence of amyloid is necessary to induce tau aggregation, leading to tau accumulation in dendritic mitochondria which may alter synapse function and contribute to accelerated cognitive decline in APP/PS1 mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Shingo Ito, Ryotaro Yagi, Seiryo Ogata, Takeshi Masuda, Takashi Saito, Takaomi Saido, Sumio Ohtsuki
Summary: This study investigates the relationship between blood-brain barrier (BBB) alterations and the progression of Alzheimer's disease (AD), focusing on the accumulation of amyloid-beta peptide (Aβ) in the brains of humanized amyloid precursor protein knock-in (APP-KI) mice. The study finds that BBB dysfunction occurs early in AD development, and changes in the BBB occur after advanced Aβ accumulation in the brain. These findings provide insights into the role of BBB alterations in AD progression.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Neurosciences
Mohammad Ejaz Ahmed, Govindhasamy Pushpavathi Selvakumar, Ramasamy Thangavel, Duraisamy Kempuraj, Sudhanshu P. Raikwar, Smita Zaheer, Shankar Iyer, Asgar Zaheer
Summary: The study demonstrates that immune checkpoint blockade of GMF function with anti-GMF antibody can effectively reduce neuroinflammation and attenuate amyloid pathology in the cortex and hippocampal CA1 region of 5XFAD mouse brain. It also suggests that pharmacological immune neutralization of GMF could be a promising neuroprotective strategy for targeting neuroinflammation and neurodegeneration in Alzheimer's disease.
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Harshitha Santhosh Kumar, James Moore, Adrian C. Steiner, Emmanuel Sotirakis, Benjamin Schaerli, Patricia Isnard-Petit, Kader Thiam, David P. Wolfer, Erik C. Boettger
Summary: This study investigates the role of protein homeostasis in the accumulation of Alzheimer's associated protein A beta and levels of associated Tau phosphorylation. Surprisingly, disruptions in protein homeostasis did not significantly affect A beta accumulation and phosphorylated Tau levels.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Multidisciplinary Sciences
Dorit Trudler, Kristopher L. Nazor, Yvonne S. Eisele, Titas Grabauskas, Nima Dolatabadi, James Parker, Abdullah Sultan, Zhenyu Zhong, Marshall S. Goodwin, Yona Levites, Todd E. Golde, Jeffery W. Kelly, Michael R. Sierks, Nicholas J. Schork, Michael Karin, Rajesh Ambasudhan, Stuart A. Lipton
Summary: Parkinson's disease is associated with the accumulation of alpha-synuclein and activation of microglia, potentially leading to neuronal death. This study shows that alpha-synuclein can activate NLRP3 inflammasome in human microglia and that alpha-synuclein-antibody complexes can exacerbate inflammation in a human context.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Chemistry, Medicinal
Arianna Burton, Adam Castano, Marianna Bruno, Steve Riley, Jennifer Schumacher, Marla B. Sultan, Sandi See Tai, Daniel P. Judge, Jignesh K. Patel, Jeffery W. Kelly
Summary: Rare diseases are considered a global public health priority, with Tafamidis representing a major breakthrough in the treatment of transthyretin amyloidosis after decades of research and clinical trials that established its safety and efficacy.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2021)
Article
Biochemistry & Molecular Biology
Jessica D. Rosarda, Kelsey R. Baron, Kayla Nutsch, Gabriel M. Kline, Caroline Stanton, Jeffery W. Kelly, Michael J. Bollong, R. Luke Wiseman
Summary: Research has shown that the small molecule proteostasis regulator AA147 can protect against glutamate-induced cell death in neuronal-derived cell culture models. This protective effect is primarily mediated through the activation of the NRF2-regulated oxidative stress response, rather than the ATF6 pathway. These findings highlight the potential of metabolically activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 signaling pathways to mitigate oxidative damage associated with various neurological diseases.
ACS CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Fabrizio Chiti, Jeffery W. Kelly
Summary: Protein misfolding diseases are caused by structural abnormalities in proteins, and specific small molecules have been approved to stabilize the folded state of these proteins, providing a promising approach to treat such diseases.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Heike Kroeger, Julia M. D. Grandjean, Wei-Chieh Jerry Chiang, Daphne D. Bindels, Rebecca Mastey, Jennifer Okalova, Amanda Nguyen, Evan T. Powers, Jeffery W. Kelly, Neil J. Grimsey, Michel Michaelides, Joseph Carroll, R. Luke Wiseman, Jonathan H. Lin
Summary: ER stress and UPR signaling contribute to human diseases, including severe congenital vision loss conditions like achromatopsia. Loss-of-function ATF6 variants lead to defective cone formation in the retina, highlighting the essential role of ATF6 in human cone development. Pharmacologic targeting of the ATF6 pathway may hold potential for treating blinding retinal diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Lucio M. Schiapparelli, Pranav Sharma, Hai-Yan He, Jianli Li, Sahil H. Shah, Daniel B. McClatchy, Yuanhui Ma, Han-Hsuan Liu, Jeffrey L. Goldberg, John R. Yates, Hollis T. Cline
Summary: This study demonstrates the existence of diverse protein transfer between neurons in the healthy brain, which may be mediated by exosomes.
Article
Chemistry, Medicinal
Nicholas L. Yan, Reji Nair, Alan Chu, Ian A. Wilson, Kristen A. Johnson, Gareth J. Morgan, Jeffery W. Kelly
Summary: This study investigates the potential of finding small molecule kinetic stabilizers in immunoglobulin light chain amyloidosis, identifying coumarin-based compounds with potential therapeutic effects. Structural-activity relationship data reveals that these compounds bind at different sites in the LC dimer, exerting unique stabilizing effects on LCs.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Biochemistry & Molecular Biology
Gabriel M. Kline, Karina Nugroho, Jeffery W. Kelly
Summary: In this review, we examine the application of Inverse Drug Discovery method using organic compounds of intermediate complexity harboring Sulfur(VI)-fluoride exchange (SuFEx) electrophiles to expand the cellular proteins that can be targeted covalently.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Meng Wang, Edmund Cotter, Ya-Juan Wang, Xu Fu, Angela L. Whittsette, Joseph W. Lynch, R. Luke Wiseman, Jeffery W. Kelly, Angelo Keramidas, Ting-Wei Mu
Summary: This study demonstrates that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis can increase the assembly, trafficking, and surface expression of variant GABA(A) receptors, offering a potential opportunity to mitigate pathology associated with genetic epilepsy and other disease-associated variant ion channels.
CELL AND BIOSCIENCE
(2022)
Article
Cell Biology
Jaleh S. Mesgarzadeh, Isabelle C. Romine, Ethan M. Smith-Cohen, Julia M. D. Grandjean, Jeffery W. Kelly, Joseph C. Genereux, R. Luke Wiseman
Summary: This study identified ER proteostasis factors involved in ATF6-dependent reductions in destabilized TTR secretion through a mass-spectrometry-based interactomics approach. Activation of ATF6 reduces the secretion and subsequent aggregation of amyloidogenic TTR through increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. PDIA4 retains destabilized TTR in the ER through a redox-independent mechanism. These findings provide a mechanistic basis for the therapeutic targeting of ATF6 activation to improve treatments for TTR-related amyloid diseases.
Article
Geriatrics & Gerontology
Mathew S. Maurer, Dia Smiley, Eli Simsolo, Fabrizio Remotti, Angela Bustamante, Sergio Teruya, Stephen Helmke, Andrew J. Einstein, Ronald Lehman, Jon T. Giles, Jeffery W. Kelly, Felix Tsai, William S. Blaner, Pierre-Jacques Brun, Ron Riesenburger, James Kryzanski, Cindy Varga, Ayan R. Patel
Summary: Lumbar spinal stenosis (LSS) is a common reason for spine surgery in older adults, with amyloid detected in over one third of patients, especially in those over 75 years old. Age, clinical symptoms, cardiac biomarkers, and other parameters did not differ significantly between patients with and without amyloid.
JOURNAL OF THE AMERICAN GERIATRICS SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Cecilia Monteiro, Jaleh S. Mesgarzadeh, Joao Anselmo, Joana Fernandes, Marta Novais, Carla Rodrigues, David L. Powers, Evan T. Powers, Teresa Coelho, Jeffery W. Kelly
Summary: This study explored the relationship between TTR stabilization markers and clinical efficacy of tafamidis treatment. The results showed an increase in native TTR concentration and a decrease in non-native TTR concentration. However, changes in native and non-native TTR levels were not correlated with clinical response to tafamidis. Successful tafamidis therapy requires moderate TTR stabilization, and male patients may benefit from higher doses of tafamidis.
AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS
(2023)
Article
Biochemical Research Methods
Emily Hashimoto-Roth, Anuradha Surendra, Mathieu Lavallee-Adam, Steffany A. L. Bennett, Miroslava Cuperlovic-Culf
Summary: This study developed an online application called META-BOA to handle class imbalance and provide assistance in data visualization and sample classification. The tool offers four different methods for class balancing and can generate a new balanced dataset to observe the augmentation effects.
Article
Neurosciences
Lucio M. Schiapparelli, Yi Xie, Pranav Sharma, Daniel B. McClatchy, Yuanhui Ma, John R. Yates III, Anton Maximov, Hollis T. Cline
Summary: Neuronal activity triggers signaling cascades that lead to structural and functional neuronal plasticity, as well as metabolic changes. By quantitatively analyzing the dynamic changes in newly synthesized proteins (NSPs) induced by activity in genetically defined cortical glutamatergic neurons, this study identified downstream mediators of neuronal plasticity.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Felix J. J. Tsai, Luke T. T. Nelson, Gabriel M. M. Kline, Marcus Jager, John L. L. Berk, Yoshiki Sekijima, Evan T. T. Powers, Jeffery W. Kelly
Summary: This study investigated the plasma concentrations of diflunisal and its efficacy in treating TTR polyneuropathy, finding that at a certain concentration, diflunisal can effectively slow down TTR dissociation rate and inhibit aggregation.
AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS
(2023)
