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
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
Multidisciplinary Sciences
Chen Jin, Jiaoni Wang, Yumeng Wang, Bojun Jia, Xuefei Guo, Guanghui Yang, Peng Xu, Paul Greengard, Rui Zhou, Yigong Shi
Summary: In this study, researchers discovered that GSAP-16K can modulate the cleavage of APP by gamma-secretase through both dilute phase and condensate formation. The dilute phase of GSAP-16K promotes the production of Aβ42, while the condensates of GSAP-16K reduce the cleavage of APP-C99. Additionally, GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings provide mechanistic insights into the modulation of gamma-secretase activity and have implications for the development of potential therapeutics for diseases like Alzheimer's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
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
Cell Biology
Magdalena Antonino, Paula Marmo, Carlos Leandro Freites, Gonzalo Emiliano Quassollo, Maria Florencia Sanchez, Alfredo Lorenzo, Elena Anahi Bignante
Summary: Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) in the brain, which is produced by the cleavage of amyloid precursor protein (APP). Aβ assemblies enhance the interaction between APP and BACE1, leading to increased production and accumulation of Aβ. This process involves Aβ-APP/Go signaling and Gβγ subunit signaling.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
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)
Review
Geriatrics & Gerontology
Jiang Chen, Jun-Sheng Chen, Song Li, Fengning Zhang, Jie Deng, Ling-Hui Zeng, Jun Tan
Summary: Decades of research have shown that amyloid-beta (Aβ) plays an undeniable role in the development of Alzheimer's disease (AD). However, the focus on the pathological effects of Aβ may overshadow the significance of its metabolic precursor, amyloid precursor protein (APP), in the occurrence and progression of AD. This review explores the various roles of APP in AD, including its structure, functions, enzymatic processing, and potential therapeutic approaches to targeting APP to ameliorate AD pathologies and halt disease progression.
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
Yan Tan, Jiani Zhang, Ke Yang, Zihui Xu, Huawei Zhang, Weihang Chen, Tiantian Peng, Xu Wang, Zhaoheng Liu, Peng Wei, Na Li, Zhenqiang Zhang, Tonghua Liu, Qian Hua
Summary: This study found that these four anti-stroke CHMs regulate A beta PP processing through different mechanisms, with T2 being a promising candidate for AD treatment.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
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
Xiaoling Liu, Yan Liu, Shangrong Ji
Summary: Alzheimer's disease is a common neurodegenerative disease that increases in prevalence with age. Studies suggest that abnormalities in the metabolism of APP are a major pathological feature of AD, with secretases playing a key role in APP processing. Research on secretases in the processing of APP could potentially lead to new directions for AD therapy.
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
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)
Review
Neurosciences
Gunnar Nordvall, Johan Lundkvist, Johan Sandin
Summary: Recent clinical data have shown that removing A beta-amyloid plaques in early Alzheimer's disease can slow down disease progression. This progress validates the amyloid cascade hypothesis and highlights the importance of targeting A beta-amyloid for therapeutic purposes. It also suggests that reducing the production of amyloidogenic A beta can prevent the formation of A beta-pathology. Further research is needed to explore the potential of gamma-secretase modulators in preventing and treating Alzheimer's disease.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Neurosciences
Alexandra A. Sandberg, Evan Manning, Heather M. Wilkins, Randall Mazzarino, Taylor Minckley, Russell H. Swerdlow, David Patterson, Yan Qin, Daniel A. Linseman
Summary: In this study, the potential of mitochondrial-targeted AICD to induce neuronal apoptosis and its mechanism of neurotoxicity were examined. The results showed that only when AICD was targeted to the mitochondria, significant neuronal apoptosis was induced. Furthermore, AICD induced apoptosis via a mechanism that is distinct from that of A beta.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Article
Genetics & Heredity
Xiangge Meng, Chengping Li, Yu Hei, Xiang Zhou, Guoli Zhou
Summary: The study used IVT-SAPAS sequencing to analyze the dynamic changes of APA sites during adipogenesis in bovine subcutaneous preadipocytes and intramuscular preadipocytes. The results showed that APA plays an important role in adipocyte differentiation, and UTR-APA switching genes have different trends, with intramuscular preadipocytes tending to use shorter 3'UTR for differentiation. TRIB3, WWTR1, and INSIG1 play important roles in intramuscular preadipocyte differentiation.
Article
Genetics & Heredity
S. Alizadeh, S. Khamse, N. Tajeddin, H. R. Khorram Khorshid, A. Delbari, M. Ohadi
Summary: This study identifies a specific genotype at a CG-rich trinucleotide short tandem repeat (STR) locus that is associated with late-onset neurocognitive disorders such as Alzheimer's disease (AD).
Article
Genetics & Heredity
Shougang Liu, Zhe Zhuang, Fanghua Liu, Xiuqing Yuan, Zeqiao Zhang, Xiaoqian Liang, Xinhui Li, Yongfeng Chen
Summary: This study investigated the effect and mechanism of RPL9 and TIFA in scalp psoriasis, and identified RPL9 as a potential therapeutic target for scalp psoriasis.
Article
Genetics & Heredity
Shiting Wang, Jiaqi Chen, Zhichao Jin, Ying Xing, Ruiping Wang
Summary: This study suggests a causal association between hair color and skin cancers, with light hair colors (red, blonde, and light brown) being associated with an increased risk and dark brown hair being associated with a decreased risk.
Article
Genetics & Heredity
Joseph Hawadak, Loick Pradel Kojom Foko, Rodrigue Roman Dongang Nana, Karmveer Yadav, Veena Pande, Aparup Das, Vineeta Singh
Summary: This study investigates the genetic diversity and natural selection of the Pfama-1 gene in Plasmodium falciparum isolates from Cameroon. The study finds a considerable nucleotide and haplotype diversity, as well as specific mutations in Cameroonian isolates. Positive diversifying selection and the identification of selected codon sites suggest the potential implication of these genetic variations in host immune pressure and parasite-binding complex modulation. The findings provide valuable baseline data for malaria vaccine design.
Article
Genetics & Heredity
Emily Biernat, Mansi Verma, Chhabi K. Govind
Summary: RSC is an essential ATP-dependent chromatin remodeling complex in Saccharomyces cerevisiae. It regulates nucleosome-depleted regions (NDRs) by sliding flanking nucleosomes away from NDRs. Depletion of RSC leads to nucleosome encroachment in NDRs and transcription initiation defects. The study compared the effects of catalytic-dead Sth1 and rapid depletion of Sth1 on transcription. Rapid depletion of Sth1 reduces recruitment of TBP and Pol II, while the catalytic-dead mutant exhibits a severe reduction in TBP binding but accumulates Pol II in coding regions. The results suggest a role for RSC in transcription elongation and termination processes.
Article
Genetics & Heredity
Yunxiao Wei, Yuhan Song, Muhammad Aamir Khan, Chengzhen Liang, Zhigang Meng, Yuan Wang, Sandui Guo, Rui Zhang
Summary: This study analyzed the GhTPP protein family in upland cotton for the first time and identified the important role of GhTPPA_2 in regulating sugar metabolism, improving soluble sugar accumulation, and drought stress tolerance.
Article
Genetics & Heredity
Yannan Geng, Rui Shao, Tiantong Xu, Lilong Zhang
Summary: A novel risk model based on SCUBE3, TNNC1, SPON1, SEPT12 and ULBP1 genes was developed for predicting PMOP risk, with higher risk score indicating higher risk of suffering from PMOP. Significant differences in signaling pathway activities were observed between the high-risk score group and the low-risk score group.
Article
Genetics & Heredity
Randy P. Williams, Corina Lesseur, Haoxiang Cheng, Qian Li, Maya Deyssenroth, Christopher D. Molteno, Ernesta M. Meintjes, Sandra W. Jacobson, Joseph L. Jacobson, Helen Wainwright, Ke Hao, Jia Chen, R. Colin Carter
Summary: The study suggests that heavy alcohol exposure during pregnancy may impact the proportion of fetal placental villi macrophages and increase the expression of inflammatory genes. Further research is needed to explore these effects and evaluate the potential functional roles of placental inflammation in FASD.
Article
Genetics & Heredity
Lvjing Luo, Lishuang Sun, Shu Li, Huiting Liu, Zhengyu Chen, Shi Huang, Yinyin Mo, Genliang Li
Summary: This study analyzed the expression of Ptpn1 and miR-124-3p in testicular tissues of mice and investigated their regulatory relationship. The results showed that Ptpn1 expression was up-regulated in adult mouse testis compared to juvenile mouse testis, while miR-124-3p expression showed an opposite pattern. Further analysis suggested that the down-regulation of miR-124-3p may contribute to the high expression of Ptpn1 in adult mouse testis.
Article
Genetics & Heredity
Gairui Li, Dan Zhao, Xiaolin Peng, Yashuang Zhao
Summary: MiRNA-22 shows potential as a candidate for early diagnosis of colorectal cancer (CRC). The study found higher miR-22 expression levels in the CRC and CRA groups, suggesting its potential as a biomarker for CRC early screening.
Article
Genetics & Heredity
Zhongqiu Zhu, Qianting Yang, Xiaoying Tian, Da Man, Jian Wang, Junfang Zhang, Bingshe Han
Summary: This study constructed a ceRNA network mediated by lncRNAs in cold-acclimated zebrafish ZF4 cells and revealed that upregulation of MSTRG3207 promotes apoptosis by sponging dre-miR-736 during cold acclimation.
Article
Genetics & Heredity
Weitao Chen, Denggao Xiang, Shang Gao, Shuli Zhu, Zhi Wu, Yuefei Li, Jie Li
Summary: Dam construction has negatively impacted the genetic diversity and structure of fish populations. This case study on the endangered Hemibagrus guttatus found low genetic diversity, high levels of inbreeding, and decreasing population size in fragmented populations. Genetic structure and differentiation were also observed, indicating the influence of dams on these fish populations.
Article
Genetics & Heredity
Pooja Singh, Debleena Guin, Bijay Pattnaik, Ritushree Kukreti
Summary: Through systematic literature review and meta-analysis, it was found that idiopathic pulmonary fibrosis is significantly associated with 222 polymorphisms in 118 genes. Four polymorphisms - rs35705950/MUC5B, rs2736100/TERT, rs2076295/DSP, and rs111521887/TOLLIP, exhibited substantial epidemiological evidence supporting their association with IPF risk.
Article
Genetics & Heredity
Jianping Zhang, Zhijun Cai, Fanzhe Feng, Yufeng Peng, Yi Cui, Yongiqing Xu
Summary: This study found that exosomes secreted by young BMSCs can promote the healing of tendon-bone interface after rotator cuff tears. These exosomes can improve extracellular matrix remodeling, osteogenic differentiation, angiogenesis, and stemness of tendon-derived stem cells (TDSCs). The exosomes from young BMSCs have better effects compared to those from aged BMSCs.