Article
Biochemistry & Molecular Biology
Courtney J. Mycroft-West, Anthony J. Devlin, Lynsay C. Cooper, Scott E. Guimond, Patricia Procter, Gavin J. Miller, Marco Guerrini, David G. Fernig, Edwin A. Yates, Marcelo A. Lima, Mark A. Skidmore
Summary: A sulphated, marine-derived glycosaminoglycan extract from the Atlantic Sea Scallop, Placopecten magellanicus shows high inhibitory potential against BACE-1 and low anticoagulant activity, making it a promising therapeutic option.
CARBOHYDRATE RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Xingxing Wang, Qinfang Shi, Arpit Kumar Pradhan, Laura Ziegon, Martin Schlegel, Gerhard Rammes
Summary: This study found that inhalative anesthetics can enhance the activity of BACE, increase the aggregation of Aβ(1-42), and modulate dendritic spine dynamics. Sevoflurane treatment leads to a decrease in dendritic spine density and nectin-3 expression in the hippocampus, while isoflurane treatment decreases spine density and attenuates LTP. Xenon does not alter dendritic spine remodeling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Noa Stern, Alexandra Gacs, Eniko Tatrai, Beata Flachner, Istvan Hajdu, Krisztina Dobi, Istvan Bagyi, Gyorgy Dorman, Zsolt Lorincz, Sandor Cseh, Attila Kigyos, Jozsef Tovari, Amiram Goldblum
Summary: Alzheimer's disease is a complex and widespread condition, currently without full understanding and cure. Simultaneously inhibiting the formation and aggregation of AChE and BACE-1 enzymes may be an effective therapeutic approach.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Jennie L. Gabriel, Michele Tinti, William Fuller, Michael L. J. Ashford
Summary: This study utilized the biotin identification proximity assay to identify the interactome of BACE1 in healthy neuronal cells, revealing its important roles in trafficking, post-translational modification, and substrates, as well as a potential novel function in sex hormone signaling and hem regulation. Data is available through ProteomeXchange with identifier PXD021464.
NEUROSCIENCE LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Chinmay Dey, Madhuparna Roy, Abhishek Dey, Somdatta Ghosh Dey
Summary: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes brain cell death and is the most common cause of dementia. Accumulation of redox cofactors like heme in amyloid plaques originating from amyloid beta (A beta) peptides has been implicated in the pathogenesis of AD.
JOURNAL OF INORGANIC BIOCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Ryan A. Dohoney, Johnson A. Joseph, Charles Baysah, Alexandra G. Thomas, Apshara Siwakoti, Tyler D. Ball, Sunil Kumar
Summary: Abberent protein-protein interactions (aPPIs) play a crucial role in pathological conditions and can be targeted for therapeutic purposes. We have developed a chromatography-free method to synthesize a highly diverse chemical library of oligopyridylamides (OPs) to enhance affinity for disease-relevant targets.
ACS CHEMICAL BIOLOGY
(2023)
Article
Geriatrics & Gerontology
Isak Martinsson, Luis Quintino, Megg G. Garcia, Sabine C. Konings, Laura Torres-Garcia, Alexander Svanbergsson, Oliver Stange, Rebecca England, Tomas Deierborg, Jia-Yi Li, Cecilia Lundberg, Gunnar K. Gouras
Summary: Alzheimer's disease is increasingly recognized as a synapse-related disease, where amyloid-beta peptide (Aβ) is implicated in causing synapse damage. Studies have shown that homeostatic synaptic plasticity mechanisms are disrupted in AD transgenic neurons, and that both APP and Aβ can influence neuronal activity.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Review
Cell Biology
Grant Pfundstein, Alexander G. Nikonenko, Vladimir Sytnyk
Summary: This review examines the interactions of cell adhesion molecules with APP and Aβ, and analyzes the critical role these proteins play in regulating APP metabolism and physiological function, as well as Aβ toxicity.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Pinky Gehlot, Sunil Kumar, Vivek Kumar Vyas, Bhanwar Singh Choudhary, Manish Sharma, Ruchi Malik
Summary: This paper reviews the use of guanidine-based novel BACE-1 inhibitors for the treatment and maintenance of Alzheimer's disease. Alzheimer's disease is an irreversible neurological disorder, and BACE-1 is an important target for its treatment. Inhibiting BACE-1 can prevent or reverse the progression of the disease.
BIOORGANIC & MEDICINAL CHEMISTRY
(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
Neurosciences
Milica Vulin, Yu Zhong, Bryan J. Maloney, Bjoern Bauer, Anika M. S. Hartz
Summary: This study suggests that the proteasome inhibitor BTZ can protect blood-brain barrier P-gp from degradation in hAPP mice, leading to a reduction in Aβ brain levels.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Review
Geriatrics & Gerontology
Jiaxuan Li, Xin Wu, Xin Tan, Shixin Wang, Ruisi Qu, Xiaofeng Wu, Zhouqing Chen, Zhong Wang, Gang Chen
Summary: This meta-analysis found that anti-A beta drugs do not have an effect on cognitive performance in AD patients, but monoclonal antibodies can delay cognitive decline. Development of other types of anti-A beta drugs should proceed with caution.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Neurosciences
Linda Hanbouch, Beatrice Schaack, Amal Kasri, Gaelle Fontaine, Eleni Gkanatsiou, Gunnar Brinkmalm, Elena Camporesi, Erik Portelius, Kaj Blennow, Gilles Mourier, Nicolas Gilles, Mark J. Millan, Catherine Marquer, Henrik Zetterberg, Lydie Boussicault, Marie-Claude Potier
Summary: Excess brain cholesterol is strongly associated with Alzheimer's disease. This study found that the presence of a cholesterol-binding site in the amyloid precursor protein (APP) regulates its processing. Mutations in this site affected the secretion of amyloid-beta peptides and produced shorter toxic peptides. Cholesterol levels also influenced the production of these peptides, with higher cholesterol resulting in increased production.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Biochemical Research Methods
Tiantian Dai, Mingyue Qiu, Hongyu Li, Mingyan Yang, Jie Gao, Xinmin Li, Jiajia Lv, Minghui Yang, Zeli Yuan, Junjun Luo
Summary: A simple and sensitive electrochemical sensor was developed for detecting BACE1 activity. A BACE1-specific peptide was modified onto an Au electrode to attach a single-strand DNA with polycytosine DNA sequence. The sensor demonstrated a linear response range from 1 to 15 U/mL and a limit of detection of 0.05 U/mL. It exhibited good performance for detecting BACE1 activity in human serum samples, suggesting its potential application in clinical diagnostics of Alzheimer's disease.
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
(2023)
Article
Geriatrics & Gerontology
Jacob W. Astroski, Leonora K. Akporyoe, Elliot J. Androphy, Sara K. Custer
Summary: Understanding the genetics of families with histories of AD is crucial in understanding the cellular processes involved in Alzheimer's disease. Mutations in the COPI complex have been found in these families, and recent studies suggest that components of the COPI complex can affect the metabolism of pathogenic AD proteins. Depletion of the COPI subunit a-COP has been shown to alter the processing of both APP and Tau, potentially leading to pathogenic changes associated with AD.
NEUROBIOLOGY OF AGING
(2021)
Article
Neurosciences
Maria A. Boylan, Chris M. Foster, Ekarin E. Pongpipat, Christina E. Webb, Karen M. Rodrigue, Kristen M. Kennedy
Summary: This study examined the effects of aging on brain signal variability, finding that BOLD variability increases with age in various cortical and subcortical regions, and is associated with poorer cognitive performance in younger to middle-aged adults.
Article
Neurosciences
Cheryl L. Grady, Jenny R. Rieck, Daniel Nichol, Karen M. Rodrigue, Kristen M. Kennedy
Summary: The study highlights the problem of limited statistical power in fMRI research due to small sample sizes. Experiment results indicate that larger sample sizes lead to decreased brain-behavior correlations and increased similarity across spatial maps. Furthermore, the multivariate approach shows advantages in the stability of brain-behavior correlations compared to univariate methods.
HUMAN BRAIN MAPPING
(2021)
Article
Neurosciences
Ekarin E. Pongpipat, Kristen M. Kennedy, Chris M. Foster, Maria A. Boylan, Karen M. Rodrigue
Summary: This study explored the impact of aging on functional connectivity during working memory tasks, and found that age did not significantly affect the task-sensitive functional connections between fronto-parietal and default mode regions. Stronger negative connectivity between these regions was associated with better working memory performance, particularly in middle-aged and older adults.
BRAIN CONNECTIVITY
(2021)
Article
Pharmacology & Pharmacy
Dianne K. Bryce, Chris M. Ware, Janice D. Woodhouse, Paul J. Ciaccio, J. Michael Ellis, Laxminarayan G. Hegde, Sabu Kuruvilla, Matthew L. Maddess, Carrie G. Markgraf, Karin M. Otte, Frederique M. Poulet, Lauren M. Timmins, Matthew E. Kennedy, Matthew J. Fell
Summary: Long-term treatment with LRRK2 kinase inhibitors in mice can lead to mild and reversible effects on lung histomorphology, highlighting the potential safety and tolerability of chronic LRRK2 kinase inhibition in Parkinson's disease (PD) treatment.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Correction
Biochemistry & Molecular Biology
Simon Dujardin, Caitlin Commins, Aurelien Lathuiliere, Pieter Beerepoot, Analiese R. Fernandes, Tarun V. Kamath, Mark B. De Los Santos, Naomi Klickstein, Diana L. Corjuc, Bianca T. Corjuc, Patrick M. Dooley, Arthur Viode, Derek H. Oakley, Benjamin D. Moore, Kristina Mullin, Dinorah Jean-Gilles, Ryan Clark, Kevin Atchison, Renee Moore, Lori B. Chibnik, Rudolph E. Tanzi, Matthew P. Frosch, Alberto Serrano-Pozo, Fiona Elwood, Judith A. Steen, Matthew E. Kennedy, Bradley T. Hyman
Article
Chemistry, Medicinal
Brandon M. Taoka, Wen-Lian Wu, Jinsong Hao, Martin Dolmaski, Hongwu Wang, Dorthy Levorse, Peter Orth, Lynn A. Hyde, Brad Smith, Maria S. Michener, Matthew E. Kennedy, Eric M. Parker, Jared N. Cumming
Summary: This paper explores the structure-activity relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors, highlighting the impact of reduced amidine basicity on Pgp, cell potency, and efficacy in preclinical in vivo animal models. The findings provide valuable insights into the mechanisms of action of these inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Mitchell H. Keylor, Anmol Gulati, Solomon D. Kattar, Rebecca E. Johnson, Ryan W. Chau, Kaila A. Margrey, Michael J. Ardolino, Cayetana Zarate, Kelsey E. Poremba, Vladimir Simov, Gregori J. Morriello, John J. Acton, Barbara Pio, Xin Yan, Rachel L. Palte, Spencer E. McMinn, Lisa Nogle, Charles A. Lesburg, Donovon Adpressa, Shishi Lin, Santhosh Neelamkavil, Ping Liu, Jing Su, Laxminarayan G. Hegde, Janice D. Woodhouse, Robert Faltus, Tina Xiong, Paul J. Ciaccio, Jennifer Piesvaux, Karin M. Otte, Harold B. Wood, Matthew E. Kennedy, David Jonathan Bennett, Erin F. DiMauro, Matthew J. Fell, Peter H. Fuller
Summary: The study successfully discovered brain-penetrant molecules with candidate-quality, high selectivity against the kinome, potency- and selectivity-enhancing design elements, and encouraging brain penetration in preclinical models.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, General & Internal
Takashi Tarumi, Neena R. Patel, Tsubasa Tomoto, Evan Pasha, Ayaz M. Khan, Kayla Kostroske, Jonathan Riley, Cynthia D. Tinajero, Ciwen Wang, Linda S. Hynan, Karen M. Rodrigue, Kristen M. Kennedy, Denise C. Park, Rong Zhang
Summary: This study investigated the effects of a 1-year aerobic exercise intervention on cognitive function, brain volume, and cortical thickness in sedentary older adults. The results showed that both aerobic exercise and stretching interventions improved cognitive performance, but did not prevent age-related brain volume loss. Improvements in cardiorespiratory fitness were positively correlated with cognitive performance and regional cortical thickness.
JOURNAL OF INTERNAL MEDICINE
(2022)
Article
Neurosciences
Xi Chen, Melissa M. Rundle, Kristen M. Kennedy, William Moore, Denise C. Park
Summary: Neuroimaging research has found two different patterns of brain activation in successful cognitive aging - maintenance of youth-like activity and compensatory novel recruitment. This study investigated these patterns in individuals who resisted age-related cognitive decline over four years. The results showed that successful agers exhibited high subsequent memory effect until very old age, while average agers had reduced subsequent memory effect starting in young-old age. Additionally, successful agers showed additional recruitment in prefrontal clusters in young-old age. This study provides evidence of the neural mechanisms underlying successful cognitive aging.
Article
Endocrinology & Metabolism
Tsubasa Tomoto, Aryan Verma, Kayla Kostroske, Takashi Tarumi, Neena R. Patel, Evan P. Pasha, Jonathan Riley, Cynthia D. Tinajero, Linda S. Hynan, Karen M. Rodrigue, Kristen M. Kennedy, Denise C. Park, Rong Zhang
Summary: This study found that one-year progressive, moderate-to-vigorous aerobic exercise training has positive effects on cerebral blood flow, central arterial stiffness, and cognitive performance. In cognitively normal older adults, aerobic exercise training increased cerebral blood flow, decreased carotid arterial stiffness and cerebrovascular resistance, and was associated with improved memory function.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2023)
Article
Multidisciplinary Sciences
Justyna A. Dobrowolska Zakaria, Randall J. Bateman, Monika Lysakowska, Ammaarah Khatri, Dinorah Jean-Gilles, Matthew E. Kennedy, Robert Vassar
Summary: This paper presents a method for measuring the metabolism of sAPP beta and sAPP alpha in humans using stable isotope labeling kinetics, immunoprecipitation, and liquid chromatography/tandem mass spectrometry. The method allows for a comprehensive study of these analytes and could provide novel insights into the pathophysiological mechanisms of Alzheimer's disease.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Medicinal
David A. Candito, Vladimir Simov, Anmol Gulati, Solomon Kattar, Ryan W. Chau, Blair T. Lapointe, Joey L. Methot, Duane E. DeMong, Thomas H. Graham, Ravi Kurukulasuriya, Mitchell H. Keylor, Ling Tong, Gregori J. Morriello, John J. Acton, Barbara Pio, Weiguo Liu, Jack D. Scott, Michael J. Ardolino, Theodore A. Martinot, Matthew L. Maddess, Xin Yan, Hakan Gunaydin, Rachel L. Palte, Spencer E. McMinn, Lisa Nogle, Hongshi Yu, Ellen C. Minnihan, Charles A. Lesburg, Ping Liu, Jing Su, Laxminarayan G. Hegde, Lily Y. Moy, Janice D. Woodhouse, Robert Faltus, Tina Xiong, Paul Ciaccio, Jennifer A. Piesvaux, Karin M. Otte, Matthew E. Kennedy, David Jonathan Bennett, Erin F. DiMauro, Matthew J. Fell, Santhosh Neelamkavil, Harold B. Wood, Peter H. Fuller, J. Michael Ellis
Summary: This article describes the optimization process of a novel LRRK2 inhibitor for the treatment of Parkinson's disease. By combining structure-based drug design with cross-coupling technologies, a unique motif with extraordinary potency and favorable CNS drug-like properties was discovered. The lead compound showed exceptional on-target potency, selectivity, and brain exposure, making it a promising candidate for preclinical studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Neurosciences
Joseph P. Hennessee, Christina E. Webb, Xi Chen, Kristen M. Kennedy, Gagan S. Wig, Denise C. Park
Summary: There is a debate about the significance of additional fMRI-measured activity in the right prefrontal cortex in older adults and whether it enhances cognition. A study with 461 adults aged 20-89 found that higher left-lateralization in the prefrontal cortex was associated with better cognitive performance in middle-aged adults, while lower laterality scores were associated with better cognition in older adults. These findings have important implications for current theories of neurocognitive aging.
Article
Clinical Neurology
M. Yuan, Kristen M. Kennedy
Summary: This study used geospatial tools and landmarks to assess environmental complexity and predict cognitive status. The results showed that street length, circuity, and points of interest were associated with dementia. Therefore, environmental complexity plays an important role in the development of Alzheimer's disease.
JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE
(2023)
Article
Neurosciences
Stephan A. Muller, Merav D. Shmueli, Xiao Feng, Johanna Tushaus, Neele Schumacher, Ryan Clark, Brad E. Smith, An Chi, Stefan Rose-John, Matthew E. Kennedy, Stefan F. Lichtenthaler
Summary: In this study, the researchers identified SEZ6 and gp130/IL6ST as physiological substrates of BACE1 in non-human-primate cerebrospinal fluid. They also found a reduction of gp130 in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. These findings provide insights into the relationship between BACE1 and gp130 in neuronal signaling and survival.
MOLECULAR NEURODEGENERATION
(2023)