Article
Environmental Sciences
Yiping Yang, Jie Zhang, Xiaobo Yang, Zhiying Li, Jian Wang, Cailing Lu, Aruo Nan, Yunfeng Zou
Summary: The study revealed that excessive exposure to manganese inhibits the expression and activity of APP and α-secretase, leading to cognitive impairment, while showing no significant effect on β-secretase.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2021)
Article
Biochemistry & Molecular Biology
Matthias Koch, Thomas Enzlein, Shu-Yu Chen, Dieter Petit, Sam Lismont, Martin Zacharias, Carsten Hopf, Lucia Chavez-Gutierrez
Summary: This study explores the mechanism that controls the processing of the amyloid precursor protein (APP) by gamma-secretases, which is crucial in determining the length of amyloid-beta (A beta) peptides and their role in Alzheimer's disease (AD) pathogenesis. The researchers found that polar interactions established by the APPC99 ectodomain (ECD) play a key role in regulating the cleavage of APP by gamma-secretases. Increasing the hydrophobicity of APPC99-ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic gamma-secretase and APP variants on A beta length. Furthermore, the study reveals that APPC99-ECD facilitates the production of longer A beta peptides caused by certain gamma-secretase inhibitors. These findings highlight the importance of the APPC99-ECD in regulating gamma-secretase activity and suggest it as a potential target for developing compounds that can selectively promote APP processing by these enzymes.
Article
Biochemistry & Molecular Biology
Meewhi Kim, Ilya Bezprozvanny
Summary: Proteolytic processing of amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease (AD), with mutations causing increased Aβ42 production. Different conformations of gamma secretase with APP affect the amyloidogenic processing of APP. Analyzing protein structure can provide insights into the preferred processing of APP in different subcellular locations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mirco Masi, Fabrizio Biundo, Andre Fiou, Marco Racchi, Alessia Pascale, Erica Buoso
Summary: The expression of APP and its cleavage enzymes, BACE1 and gamma-secretase, has been found to increase following TBI, suggesting a link between TBI and AD. TBI is recognized as a risk factor for neurodegenerative diseases including AD. This study explores the roles of APP cleavage fragments in both physiological and pathological contexts and proposes a neuroprotective interaction network involving RACK1 and PKC beta II/ nELAV/VEGF, suggesting potential vasculogenic-targeting therapies for AD and TBI.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Meewhi Kim, Ilya Bezprozvanny
Summary: Proteolytic processing of amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease (AD). Mutations in APP, PS1, or PS2 affect APP proteolysis by gamma-secretase and influence the levels of A beta 40 and A beta 42 peptides. This paper proposes a mechanistic hypothesis that may reconcile conflicting ideas and observations regarding the role of A beta peptides and gamma-secretase in AD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucia Chavez-Gutierrez
Summary: This study investigates the interactions between an imidazole-based GSM and its target gamma-secretase-APP, and reveals that a part of the modulator interacts with a binding site on gamma-secretase, triggering rearrangements and stabilizing enzyme-substrate interactions.
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
Clinical Neurology
Yinan Yao, Seong Su Kang, Yiyuan Xia, Zhi-Hao Wang, Xia Liu, Thorsten Muller, Yi E. Sun, Keqiang Ye
Summary: The truncated APP C586-695 fragment binds directly to the inflammatory transcription factor CEBPB, enhancing its transcriptional activity and exacerbating Alzheimer's disease-related gene expression and pathogenesis.
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
Biochemistry & Molecular Biology
Nipun Chopra, Ruizhi Wang, Bryan Maloney, Kwangsik Nho, John S. Beck, Naemeh Pourshafie, Alexander Niculescu, Andrew J. Saykin, Carlo Rinaldi, Scott E. Counts, Debomoy K. Lahiri
Summary: The study found that miR-298 may have potential therapeutic effects on Alzheimer's disease by inhibiting the expression of key proteins and influencing posttranslational levels of tau protein. This research opens up new possibilities for miR-298 to become a target for Alzheimer's disease therapy.
MOLECULAR PSYCHIATRY
(2021)
Article
Biochemistry & Molecular Biology
Nana Bie, Jingyao Li, Chenjing Li, Rui Lian, Liehao Qin, Chunling Wang
Summary: The study found that DHA improved cognitive function in mice by enhancing learning and memory, reducing neuronal damage, increasing unsaturated fatty acid levels, and inhibiting amyloid plaque and tau protein deposition.
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
Cell Biology
Maria Pagnon de la Vega, Vilmantas Giedraitis, Wojciech Michno, Lena Kilander, Goekhan Guener, Mara Zielinski, Malin Lowenmark, RoseMarie Brundin, Torsten Danfors, Linda Soderberg, Irina Alafuzoff, Lars N. G. Nilsson, Anna Erlandsson, Dieter Willbold, Stephan A. Mueller, Gunnar F. Schroeder, Jorg Hanrieder, Stefan F. Lichtenthaler, Lars Lannfelt, Dag Sehlin, Martin Ingelsson
Summary: Point mutations in the APP gene cause familial Alzheimer's disease by altering A beta generation or conformation. The Uppsala APP mutation is the first reported deletion causing autosomal dominant AD, leading to early symptom onset and rapid disease progression. This mutation affects APP processing and accelerates the formation of unique fibrils and amyloid plaques in the brain.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Laura Garcia-Gonzalez, Jean-Michel Paumier, Laurence Louis, Dominika Pilat, Anne Bernard, Delphine Stephan, Nicolas Jullien, Frederic Checler, Emmanuel Nivet, Michel Khrestchatisky, Kevin Baranger, Santiago Rivera
Summary: The study revealed that MT5-MMP has control over the processing of APP and the release of Aβ through both proteolytic and non-proteolytic mechanisms, suggesting new insights for therapeutic regulation of AD-related pathology.
Article
Multidisciplinary Sciences
Naoto Watamura, Kaori Sato, Gen Shiihashi, Ayami Iwasaki, Naoko Kamano, Mika Takahashi, Misaki Sekiguchi, Naomi Mihira, Ryo Fujioka, Kenichi Nagata, Shoko Hashimoto, Takashi Saito, Toshio Ohshima, Takaomi C. Saido, Hiroki Sasaguri
Summary: Devoid of the Swedish mutations, the newly generated App knock-in mice (App(G-F) mice) show characteristics suitable for preclinical studies of beta-secretase inhibition in Alzheimer's disease (AD). Comparison of isogenic App knock-in lines reveals the influence of factors like C-terminal fragment beta (CTF-beta) and humanization of A beta on endosomal alterations.
