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
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
Jiang Chen, Anran Fan, Song Li, Yan Xiao, Yanlin Fu, Jun-Sheng Chen, Dan Zi, Ling-Hui Zeng, Jun Tan
Summary: Alzheimer's disease (AD), the most common type of dementia, is characterized by the presence of extracellular senile plaques composed of beta-amyloid peptides and intracellular neurofibrillary tangles containing phosphorylated-tau protein. This study has demonstrated the interaction between soluble tau and the N-terminal of amyloid precursor protein (APP) in vitro and in vivo, as well as the involvement of APP in the cellular uptake of tau through endocytosis. Targeting the pathological interaction between N-terminal APP and tau could be a promising therapeutic strategy for AD.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Cell Biology
Bo Zhou, Jacqueline G. Lu, Alberto Siddu, Marius Wernig, Thomas C. Sudhof
Summary: The APP-Swedish mutation in familial Alzheimer's disease enhances the production of Aβ peptides, leading to an increase in synaptic connectivity. This finding is consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in Alzheimer's disease and suggests that elevated Aβ concentrations have long-term effects on disease pathogenesis.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
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
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
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
Neurosciences
Carlos M. Soto-Faguas, Paula Sanchez-Molina, Carlos A. Saura
Summary: Mutations in presenilin genes accelerate amyloid-beta and tau pathologies in Alzheimer's disease. PS deficiency in mice leads to brain atrophy, inflammation, and accumulation of pathological tau. Inactivating PS genes exacerbates memory deficits in Tau transgenic mice by accelerating tau phosphorylation and aggregation. Tau aggregation and phosphorylation play key roles in neurodegeneration linked to familial AD.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
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
Biochemistry & Molecular Biology
Svetlana Sharifulina, Andrey Khaitin, Valeria Guzenko, Yuliya Kalyuzhnaya, Valentina Dzreyan, Alexandr Logvinov, Natalia Dobaeva, Yan Li, Lei Chen, Bin He, Svetlana Demyanenko
Summary: Our studies uncover changes in the expression of key components involved in amyloid precursor protein (APP) processing in neurons and astrocytes after photothrombotic stroke (PTS). We demonstrate an increase in N- and C-terminal fragments of APP in the cytoplasm of ischemic penumbra cells 24 hours after PTS, along with their co-immunoprecipitation with caveolin-1. The level of ADAM10 alpha-secretase decreases in the rat brain cortex on the first day after PTS. In astrocytes, but not in neurons, levels of gamma-secretase complex proteins presenilin-1 and nicastrin are elevated in the penumbra after PTS. These changes result in neuronal death and astrocyte activation during the early recovery period after PTS. Inhibiting caveolin-1 shifts APP processing towards Aβ synthesis, leading to astroglial activation. Inhibiting gamma-secretase down-regulates glial fibrillary acidic protein (GFAP) in astrocytes, prevents apoptosis in mouse cerebral cortex cells induced by PTS, and reduces the size of the infarcted area. Hence, novel gamma-secretase inhibitors hold promise as potential therapeutics for stroke treatment.
Article
Multidisciplinary Sciences
Kevin A. Murray, Carolyn J. Hu, Sarah L. Griner, Hope Pan, Jeannette T. Bowler, Romany Abskharon, Gregory M. Rosenberg, Xinyi Cheng, Paul M. Seidler, David S. Eisenberg
Summary: Neurodegenerative diseases are characterized by the accumulation of aggregated proteins, and inhibiting the formation of these aggregates is a potential therapeutic strategy. Using de novo protein design, researchers have developed a library of mini-protein inhibitors that specifically target the amyloid structures of tau, Aβ, and α Syn. These inhibitors show promising results in preventing aggregation and rescuing motor deficits in animal models of PD and AD.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Clinical Neurology
Guilian Xu, Brittany S. Ulm, John Howard, Susan E. Fromholt, Qing Lu, Brian Benedict Lee, Ariel Walker, David R. Borchelt, Jada Lewis
Summary: The study aims to investigate the pathological interaction between amyloidosis and tauopathy in Alzheimer's disease, and found that the development of tauopathy is exacerbated by the presence of newly forming amyloid deposits in younger brains and mature deposits in older brains.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(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
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.
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)