Review
Biochemistry & Molecular Biology
Vladimir Rudajev, Jiri Novotny
Summary: This article discusses the relationship between cholesterol and the development of Alzheimer's disease, as well as the influence of cholesterol on the production of amyloid beta (Aβ).
CELL AND BIOSCIENCE
(2023)
Article
Cell Biology
Sandra Roselli, Tugce Munise Satir, Rafael Camacho, Stefanie Fruhwurth, Petra Bergstrom, Henrik Zetterberg, Lotta Agholme
Summary: Alzheimer's disease (AD) is characterized by the presence of amyloid beta (Aβ)-containing plaques. The production of Aβ from amyloid precursor protein (APP) by secretases has been extensively studied, but the exact mechanism of how the interaction between APP and secretases affects APP processing is not fully understood.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Neurosciences
Lauren Owens, Joshua Bracewell, Alexandre Benedetto, Neil Dawson, Christopher Gaffney, Edward Parkin
Summary: In this study, the depletion of sA beta PP alpha and the accumulation of sA beta PP alpha' were found to contribute to cytotoxicity in AD-related neuroblastoma cells overexpressing BACE1. These findings provide new insights into the pathological mechanisms of AD and raise questions about previous studies using 6E10 antibody as a biomarker.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Article
Clinical Neurology
Yaqi Wang, Yuting Cui, Jing Liu, Qiao Song, Min Cao, Yuli Hou, Xiaomin Zhang, Peichang Wang
Summary: The upregulation of KLF5 is found to positively regulate BACE1 and accelerate APP amyloidogenic cleavage in Alzheimer's disease (AD) progression. The levels of KLF5 significantly increase in AD patients and APP/PS1 mice, and are closely related to cognitive capacity. KLF5 promotes amyloidogenic metabolism and AP synthesis through BACE1.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Clinical Neurology
Eric McDade, Iryna Voytyuk, Paul Aisen, Randall J. Bateman, Maria C. Carrillo, Bart De Strooper, Christian Haass, Eric M. Reiman, Reisa Sperling, Pierre N. Tariot, Riqiang Yan, Colin L. Masters, Robert Vassar, Stefan E. Lichtenthaler
Summary: All phase III trials of BACE inhibitors for Alzheimer disease have been discontinued or produced negative results. However, the authors believe that BACE inhibitors still hold promise as a preventative therapy for AD and suggest a series of experiments to inform future trials. The authors also discuss the status of BACE inhibitors and propose ways in which the results of discontinued trials can inform the development of future clinical trials.
NATURE REVIEWS NEUROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ruta Dekeryte, Zara Franklin, Claire Hull, Lorenzo Croce, Sarah Kamli-Salino, Oliver Helk, Philip A. Hoffmann, Zhixiang Yang, Gernot Riedel, Mirela Delibegovic, Bettina Platt
Summary: The study demonstrates the role of BACE1 in regulating systemic glucose homeostasis and suggests BACE1 inhibitors for treating T2DM-associated pathologies. LY2886721 treatment improved glucose homeostasis and hepatic insulin sensitivity in PLB4 mice, but did not show improvements in motor coordination.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Cell Biology
Lou Fourriere, Ellie Hyun-Jung Cho, Paul A. Gleeson
Summary: This study examined the segregation of BACE1 and APP in the Golgi apparatus using high-resolution microscopy techniques. The results showed that BACE1 and APP are segregated throughout the Golgi stack, while the transferrin receptor colocalizes with BACE1 but not APP.
Article
Cell Biology
Barbara Bettegazzi, Laura Sebastian Monasor, Serena Bellani, Franca Codazzi, Lisa Michelle Restelli, Alessio Vittorio Colombo, Nikolaus Deigendesch, Stephan Frank, Takashi Saito, Takaomi C. Saido, Sven Lammich, Sabina Tahirovic, Fabio Grohovaz, Daniele Zacchetti
Summary: The study provides evidence for the role of Casein Kinase 2 in controlling BACE1 expression and demonstrates a mechanism linking neuronal activity with amyloid production and deposition in the brain. The findings offer new perspectives for AD treatment strategies.
CELL DEATH & DISEASE
(2021)
Article
Neurosciences
Yuping Hao, Lingzhan Shao, Jianan Hou, Yan Zhang, Yuqian Ma, Jinhao Liu, Chuan Xu, Fujun Chen, Li-Hui Cao, Yong Ping
Summary: This study found that the natural polyphenolic phytochemical resveratrol (RES) improves sleep and courtship memory in a Drosophila model of Alzheimer's disease (AD) by activating sirtuin 1 (Sirt1/Sir2), and reduces behavioral deficits and A beta burden.
NEUROSCIENCE BULLETIN
(2023)
Article
Neurosciences
Jonathan Aow, Tzu-Rung Huang, Gopal Thinakaran, Edward H. Koo
Summary: In this study, the researchers found that there was a significant early and aberrant Bace1-mediated APP cleavage in the presence of APP/Bace1 co-expression. This led to disturbances in the trafficking of full-length APP (fl-APP) from the secretory pathway, resulting in a substantial loss of surface fl-APP and a marked reduction in APP internalization. Therefore, caution is needed when interpreting results where APP is detected only with a C-terminal tag in the presence of Bace1 co-expression, and previous findings may need to be reinterpreted if it is unclear whether fl-APP is present in normal physiological levels.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Oncology
Qing-Qing Xie, Xiao Feng, Yi-Yun Huang, Nian Fang, Hua Yi, Zi-Jian Wang, Qiao-Yu Cao, Guo-Feng Lou, Jun-Ping Pan, Yang Hu, Fang-Cheng Li, Qing Zheng, Fei Xiao
Summary: The study suggests that Nogo-A may be involved in Alzheimer's disease by promoting beta-amyloid protein secretion, potentially providing a new target for therapy. Nogo-A is known for its role as an inhibitor of neuron regeneration in the adult central nervous system, and further research is needed to understand its molecular mechanisms in Alzheimer's disease.
MOLECULAR MEDICINE REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Xuansheng Xiao, Xiaotong Wang, Ke Zhu, Lijuan Li, Ying He, Jinglan Zhang, Linying Li, Hanning Hu, Yanqiu Cui, Jianliang Zhang, Yan Zheng
Summary: BACE1 is a key enzyme involved in the production of β-amyloid, and is considered a major drug target for Alzheimer's disease. However, BACE1 inhibitors have failed in clinical trials, and may actually worsen cognitive function, suggesting that BACE1 may play a role in regulating cognition-relevant neural circuits.
MOLECULAR PSYCHIATRY
(2023)
Article
Cell Biology
Tobias A. Weber, Johan Lundkvist, Johanna Wanngren, Hlin Kvartsberg, ShaoBo Jin, Pia Larssen, Dan Wu, Daniel Oliveira, Karolina Minta, Gunnar Brinkmalm, Henrik Zetterberg, Kaj Blennow, Gunnar Nordvall, Bengt Winblad, Erik Portelius, Helena Karlstrom
Summary: The study demonstrates that gamma-secretase modulators selectively affect the production of Aβ, with a particular modulation on the Aβ-like proteins derived from EphA4.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Ryota Suzuki, Haruka Takahashi, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Eugene Futai
Summary: In this study, the APP mutation T714I, which is associated with familial Alzheimer's disease, was found to severely reduce the cleavage of A beta. Secondary mutations were identified that restored the cleavage of APP T714I and could modulate the production of A beta species in mammalian cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Claudia Capitini, Alessandra Bigi, Niccolo Parenti, Marco Emanuele, Niccolo Bianchi, Roberta Cascella, Cristina Cecchi, Laura Maggi, Francesco Annunziato, Francesco Saverio Pavone, Martino Calamai
Summary: High cholesterol levels increase the shedding of amyloid precursor protein (APP) in human neuroblastoma cells, affecting its cleavage by Bace1. However, cholesterol enrichment does not affect the lateral diffusion of APP and Bace1, as demonstrated by single molecule tracking.
Article
Immunology
Julie Oniszczuk, Kelhia Sendeyo, Cerina Chhuon, Berkan Savas, Etienne Cogne, Pauline Vachin, Carole Henique, Ida Chiara Guerrera, Giuseppe Astarita, Vincent Frontera, Andre Pawlak, Vincent Audard, Dil Sahali, Mario Ollero
CELLULAR & MOLECULAR IMMUNOLOGY
(2020)
Meeting Abstract
Endocrinology & Metabolism
Julie C. Ullman, Alicia A. Nugent, Annie Arguello, Akhil Bhalla, Thomas Sandmann, Steve Lianoglou, Connie Ha, Junhua Wang, Sonnet S. Davis, Jamal Alkabsh, Giuseppe Astarita, Gilbert Di Paolo, Tina Giese, Cathal Mahon, Catherine Bedard, Nicholas Liang, Gunasekaran Kannan, Joesph W. Lewcock, Zachary K. Sweeney, Mihalis S. Kariolis, Dolo Diaz, Anastasia Henry
MOLECULAR GENETICS AND METABOLISM
(2020)
Meeting Abstract
Endocrinology & Metabolism
Anastasia G. Henry, Julie Ullman, Annie Arguello, Jennifer Getz, Akhil Bhalla, Cathal Mahon, Junhua Wang, Tina Giese, Catherine Bedard, Jessica Blumenfeld, Ritesh Ravi, Alicia Nugent, Steve Lianoglou, Mark Dennis, Kannan Gunasekaran, Ankita Srivastava, Kirk Henne, Robert Thorne, Gilbert Di Paolo, Giuseppe Astarita, Dolores Diaz, Adam Silverman, Ryan Watts, Zachary Sweeney, Mihalis Kariolis
MOLECULAR GENETICS AND METABOLISM
(2020)
Article
Neurosciences
Alicia A. Nugent, Karin Lin, Bettina van Lengerich, Steve Lianoglou, Laralynne Przybyla, Sonnet S. Davis, Ceyda Llapashtica, Junhua Wang, Do Jin Kim, Dan Xia, Anthony Lucas, Sulochanadevi Baskaran, Patrick C. G. Haddick, Melina Lenser, Timothy K. Earr, Ju Shi, Jason C. Dugas, Benjamin J. Andreone, Todd Logan, Hilda O. Solanoy, Hang Chen, Ankita Srivastava, Suresh B. Poda, Pascal E. Sanchez, Ryan J. Watts, Thomas Sandmann, Giuseppe Astarita, Joseph W. Lewcock, Kathryn M. Monroe, Gilbert Di Paolo
Article
Cell Biology
Julie C. Ullman, Annie Arguello, Jennifer A. Getz, Akhil Bhalla, Cathal S. Mahon, Junhua Wang, Tina Giese, Catherine Bedard, Do Jin Kim, Jessica R. Blumenfeld, Nicholas Liang, Ritesh Ravi, Alicia A. Nugent, Sonnet S. Davis, Connie Ha, Joseph Duque, Hai L. Tran, Robert C. Wells, Steve Lianoglou, Vinay M. Daryani, Wanda Kwan, Hilda Solanoy, Hoang Nguyen, Timothy Earr, Jason C. Dugas, Michael D. Tuck, Jennifer L. Harvey, Michelle L. Reyzer, Richard M. Caprioli, Sejal Hall, Suresh Poda, Pascal E. Sanchez, Mark S. Dennis, Kannan Gunasekaran, Ankita Srivastava, Thomas Sandmann, Kirk R. Henne, Robert G. Thorne, Gilbert Di Paolo, Giuseppe Astarita, Dolores Diaz, Adam P. Silverman, Ryan J. Watts, Zachary K. Sweeney, Mihalis S. Kariolis, Anastasia G. Henry
SCIENCE TRANSLATIONAL MEDICINE
(2020)
Article
Biochemistry & Molecular Biology
Akhil Bhalla, Ritesh Ravi, Meng Fang, Annie Arguello, Sonnet S. Davis, Chi-Lu Chiu, Jessica R. Blumenfeld, Hoang N. Nguyen, Timothy K. Earr, Junhua Wang, Giuseppe Astarita, Yuda Zhu, Damian Fiore, Kimberly Scearce-Levie, Dolores Diaz, Heather Cahan, Matthew D. Troyer, Jeffrey M. Harris, Maria L. Escolar
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Biochemistry & Molecular Biology
Junhua Wang, Akhil Bhalla, Julie C. Ullman, Meng Fang, Ritesh Ravi, Annie Arguello, Elliot Thomsen, Buyankhishig Tsogtbaatar, Jing L. Guo, Lukas L. Skuja, Jason C. Dugas, Sonnet S. Davis, Suresh B. Poda, Kannan Gunasekaran, Simona Costanzo, Zachary K. Sweeney, Anastasia G. Henry, Jeffrey M. Harris, Kirk R. Henne, Giuseppe Astarita
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Neurosciences
Benjamin J. Andreone, Laralynne Przybyla, Ceyda Llapashtica, Anil Rana, Sonnet S. Davis, Bettina van Lengerich, Karin Lin, Ju Shi, Yuan Mei, Giuseppe Astarita, Gilbert Di Paolo, Thomas Sandmann, Kathryn M. Monroe, Joseph W. Lewcock
NATURE NEUROSCIENCE
(2020)
Article
Clinical Neurology
Grace F. Crotty, Romeo Maciuca, Eric A. Macklin, Junhua Wang, Manuel Montalban, Sonnet S. Davis, Jamal Alkabsh, Rachit Bakshi, Xiqun Chen, Alberto Ascherio, Giuseppe Astarita, Sarah Huntwork-Rodriguez, Michael A. Schwarzschild
Review
Biochemistry & Molecular Biology
Berkan Savas, Giuseppe Astarita, Massimo Aureli, Dil Sahali, Mario Ollero
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Review
Spectroscopy
Giuseppe Paglia, Andrew J. Smith, Giuseppe Astarita
Summary: Researchers are utilizing ion mobility mass spectrometry (IM-MS) for metabolomics and lipidomics applications, which offers advantages such as measuring collision cross-section values, improving peak capacity and signal-to-noise ratio, and coupling with various fragmentation modes. These advancements provide a more robust tool for identification, quantification, and structural characterization in the field.
MASS SPECTROMETRY REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Todd Logan, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, Chi-Lu Chiu, Meng Fang, Fen Huang, Akhil Bhalla, Ceyda Llapashtica, Rachel Prorok, Michelle E. Pizzo, Meredith E. K. Calvert, Elizabeth W. Sun, Jennifer Hsiao-Nakamoto, Yashas Rajendra, Katrina W. Lexa, Devendra B. Srivastava, Bettina van Lengerich, Junhua Wang, Yaneth Robles-Colmenares, Do Jin Kim, Joseph Duque, Melina Lenser, Timothy K. Earr, Hoang Nguyen, Roni Chau, Buyankhishig Tsogtbaatar, Ritesh Ravi, Lukas L. Skuja, Hilda Solanoy, Howard J. Rosen, Bradley F. Boeve, Adam L. Boxer, Hilary W. Heuer, Mark S. Dennis, Mihalis S. Kariolis, Kathryn M. Monroe, Laralynne Przybyla, Pascal E. Sanchez, Rene Meisner, Dolores Diaz, Kirk R. Henne, Ryan J. Watts, Anastasia G. Henry, Kannan Gunasekaran, Giuseppe Astarita, Jung H. Suh, Joseph W. Lewcock, Sarah L. DeVos, Gilbert Di Paolo
Summary: Mutations in the GRN gene lead to frontotemporal dementia, with a deficiency in the PGRN protein being the cause. Research found various abnormalities in Grn(-/-) mice, including a lack of endolysosomal phospholipids and accumulation of glucocerebrosidase substrate. A protein replacement strategy corrected these abnormalities and may represent a potential biotherapeutic for GRN-FTD.
Article
Neurosciences
Dan Xia, Steve Lianoglou, Thomas Sandmann, Meredith Calvert, Jung H. Suh, Elliot Thomsen, Jason Dugas, Michelle E. Pizzo, Sarah L. DeVos, Timothy K. Earr, Chia-Ching Lin, Sonnet Davis, Connie Ha, Amy Wing-Sze Leung, Hoang Nguyen, Roni Chau, Ernie Yulyaningsih, Isabel Lopez, Hilda Solanoy, Shababa T. Masoud, Chun-chi Liang, Karin Lin, Giuseppe Astarita, Nathalie Khoury, Joy Yu Zuchero, Robert G. Thorne, Kevin Shen, Stephanie Miller, Jorge J. Palop, Dylan Garceau, Michael Sasner, Jennifer D. Whitesell, Julie A. Harris, Selina Hummel, Johannes Gnorich, Karin Wind, Lea Kunze, Artem Zatcepin, Matthias Brendel, Michael Willem, Christian Haass, Daniel Barnett, Till S. Zimmer, Anna G. Orr, Kimberly Scearce-Levie, Joseph W. Lewcock, Gilbert Di Paolo, Pascal E. Sanchez
Summary: This study created a novel App knock-in mouse model and found that microglia with fibrillar A beta were associated with lipid dyshomeostasis, lysosomal dysfunction, foam cell phenotypes, and immuno-metabolic perturbations, offering new avenues for investigating metabolic pathways in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this model provides a valuable resource for further research on disease-relevant biology.
MOLECULAR NEURODEGENERATION
(2022)
Article
Cell Biology
Danna Jennings, Sarah Huntwork-Rodriguez, Anastasia G. Henry, Jennifer C. Sasaki, Rene Meisner, Dolores Diaz, Hilda Solanoy, Xiang Wang, Elvira Negrou, Vitaliy V. Bondar, Rajarshi Ghosh, Michael T. Maloney, Nicholas E. Propson, Yuda Zhu, Romeo D. Maciuca, Laura Harris, Angela Kay, Peter LeWitt, T. Alex King, Drew Kern, Aaron Ellenbogen, Ira Goodman, Andrew Siderowf, Jason Aldred, Omid Omidvar, Shababa T. Masoud, Sonnet S. Davis, Annie Arguello, Anthony A. Estrada, Javier de Vicente, Zachary K. Sweeney, Giuseppe Astarita, Marie T. Borin, Bradley K. Wong, Harvey Wong, Hoang Nguyen, Kimberly Scearce-Levie, Carole Ho, Matthew D. Troyer
Summary: Mutations in LRRK2 are common genetic risk factors for Parkinson's disease. Inhibition of LRRK2 with DNL201 has shown positive effects in preclinical and clinical trials, improving lysosomal function and demonstrating safety and tolerability. Further development of LRRK2 inhibitors as a therapeutic modality for Parkinson's disease is warranted.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Review
Pharmacology & Pharmacy
Giuseppe Astarita, Rachel S. Kelly, Jessica Lasky-Su
Summary: Metabolomics and lipidomics play a crucial role in drug discovery and development by providing functional insights through monitoring changes in metabolites and lipids, and promising a transformative impact on precision medicine.
DRUG DISCOVERY TODAY
(2023)