Article
Biochemistry & Molecular Biology
Gee Euhn Choi, Ji Yong Park, Mo Ran Park, Jee Hyeon Yoon, Ho Jae Han
Summary: The release of glucocorticoid induced by stress is an important factor in the formation of amyloid, which increases the levels of amyloid precursor protein (APP) and beta secretase 1 (BACE1). Glucocorticoid also contributes to the development of Alzheimer's disease (AD) by promoting the connection between the endoplasmic reticulum (ER) and mitochondria, where amyloid beta (Aβ) is processed due to its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances gamma-secretase activity in the mitochondrial-associated membrane of ER (MAM) and leads to the accumulation of mitochondrial Aβ remains unclear.
Article
Neurosciences
Masato Maesako, Mei C. Q. Houser, Yuliia Turchyna, Michael S. Wolfe, Oksana Berezovska
Summary: In this study, we used a novel imaging method to visualize the subcellular compartment where γ-secretase primarily cleaves C99 to generate Aβ in mouse cortical neurons. Our findings suggest that γ-secretase processes C99 mainly in low-pH compartments and Aβ is accumulated in the same subcellular loci. Additionally, we found a functional correlation between endo-lysosomal pH and cellular γ-secretase activity.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Maria-Angeles Cortes-Gomez, Victor M. Barbera, Jordi Alom, Javier Saez-Valero, Maria-Salud Garcia-Ayllon
Summary: In Alzheimer's disease, the inactive and active forms of acetylcholinesterase (AChE) exhibit differences in their glycosylation pattern, particularly in the presence of terminal mannoses in the active forms. Sporadic AD patients have reduced binding to terminal mannoses compared to non-demented individuals, while familial AD patients with PSEN1 gene mutations have higher binding. Furthermore, presenilin-1 (PS1) modulates AChE trafficking and maturation in Golgi regions, promoting the presence of active forms in the cell membrane.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, Research & Experimental
Jihoon Han, Heejin Park, Chinmoyee Maharana, A-Ryeong Gwon, Jinsu Park, Seung Hyun Baek, Han-Gyu Bae, Yoonsuk Cho, Hark Kyun Kim, Jae Hoon Sul, Jeongmi Lee, Eunae Kim, Junsik Kim, Yongeun Cho, Sunyoung Park, Leon F. Palomera, Thiruma Arumugam, Mark P. Mattson, Dong-Gyu Jo
Summary: The five FAD-linked PS1 mutations have been shown to have deleterious effects on mitochondrial functions in different ways. Each PS1 mutant affected mitochondrial morphology and function differently, with some inducing mitochondrial fragmentation while others increased MAMs formation and oxidative stress. These mutations compromised mitochondrial membrane potential and ATP production, which may contribute to an accelerated age of disease onset in individuals with mutant PS1.
Article
Geriatrics & Gerontology
Shigeki Kawabata
Summary: The amyloid hypothesis for Alzheimer's disease has been widely accepted, but there is still debate over whether there is enough evidence to definitively consider amyloid-beta as a causative substance of AD.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Heewon Bae, Kyu Hwan Shim, Jang Yoo, Young-Soon Yang, Seong Soo A. An, Min-Ju Kang
Summary: The etiology of early-onset Alzheimer's disease (EOAD) is linked to mutations in the APP, PSEN1, and PSEN2 genes, leading to alterations in the production of amyloid beta (A beta) species. A 64-year-old woman with memory decline and a family history of Alzheimer's dementia was found to have mutations in APP (rs761339914; c.G1651A; p.V551M) and PSEN2 (rs533813519; c.C505A; p.H169N). These mutations affect protein interactions and intramolecular processes, potentially influencing A beta production and causing synergistic effects when combined. Further functional studies are needed to understand the pathological effects of these double mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Geriatrics & Gerontology
Kun Zou, Sadequl Islam, Yang Sun, Yuan Gao, Tomohisa Nakamura, Hiroto Komano, Taisuke Tomita, Makoto Michikawa
Summary: The study suggests that dysfunction of PS may reduce intracellular ferritin levels, leading to increased susceptibility to oxidative damage, and may be involved in the pathogenesis of Alzheimer's disease.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Cell Biology
Zenghui Teng, Georgia-Ioanna Kartalou, Sushma Dagar, Patrick C. Fraering, Volkmar Lessmann, Kurt Gottmann
Summary: The molecular mechanisms of synaptotoxic Aβ oligomers and their role in synaptic dysfunction are not fully understood. This study found that C-terminal fragments of synaptic adhesion proteins can induce a delay in synaptic vesicle endocytosis, leading to enhanced Aβ synaptotoxicity. Furthermore, delaying endocytosis can also enhance the synaptotoxicity of Aβ oligomers by promoting their binding to synaptic vesicle membranes.
CELL DEATH DISCOVERY
(2023)
Article
Neurosciences
Ye-Ran Wang, Meng-Ting Wang, Xiao-Qin Zeng, Yu-Hui Liu, Yan-Jiang Wang
Summary: This study found lower plasma levels of NAbs-PS1 in AD patients, which were negatively associated with brain A beta load and positively associated with cognitive functions. Plasma NAbs-PS1 could be potential biomarkers for distinguishing AD patients from non-AD cognitive impairment subjects.
JOURNAL OF ALZHEIMERS DISEASE
(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)
Article
Neurosciences
Ana C. Sanchez-Hidalgo, Francisco Arias-Arag, M. Teresa Romero-Barrag, Celia Martin-Cuevas, Jose M. Delgado-Garcia, Amalia Martinez-Mir, Francisco G. Scholl
Summary: The study indicates that dysfunction in PS/gamma-secretase complex may lead to neuronal deficits in familial Alzheimer's disease. Transgenic mice models in the research show an association between the accumulation of NrxnCTF and impairments in associative memory and short-term synaptic plasticity.
EXPERIMENTAL NEUROLOGY
(2022)
Article
Neurosciences
Haitao Li, Yu Li, Wenping Liang, Zheng Z. Wei, Xuanyu Li, Yuanruhua Tian, Shanshan Qiao, Yishu Yang, Liu Yang, Dongyue Wu, Wei Yin, Honglin Liu, Wei Zhang, Yongbo Zhang, Zhe Wang
Summary: A novel PSEN1 p.Tyr159Ser mutation associated with early-onset Alzheimer's disease (EOAD) was identified. The mutation caused a significant increase in the Aβ42/Aβ40 ratio and had a notable impact on PS1 maturation. Other mutations or SNPs in different genes may modify the effects of this mutation, and their identification could facilitate the discovery of AD-preventing mechanisms and methods.
MOLECULAR AND CELLULAR NEUROSCIENCE
(2022)
Article
Geriatrics & Gerontology
Yuan Gao, Yang Sun, Sadequl Islam, Tomohisa Nakamura, Taisuke Tomita, Kun Zou, Makoto Michikawa
Summary: Alzheimer's disease (AD) is associated with the accumulation of amyloid beta-protein 1-42 (A beta 42) in the brain. Angiotensin-converting enzyme (ACE) can convert neurotoxic A beta 42 to neuroprotective A beta 40 in a glycosylation-dependent manner. Mutations in the PSEN1 gene are the main cause of familial AD and lead to an increased A beta 42/40 ratio, but the mechanism behind this is still unclear.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Geriatrics & Gerontology
Diana Pendin, Cristina Fasolato, Emy Basso, Riccardo Filadi, Elisa Greotti, Luisa Galla, Chiara Gomiero, Alessandro Leparulo, Nelly Redolfi, Elena Scremin, Nicola Vajente, Tullio Pozzan, Paola Pizzo
Summary: Alzheimer's disease is a common cause of dementia in the elderly, with familial and non-familial cases. Studies focusing on the Aβ pathway have not been successful in modifying disease progression, indicating the presence of other pathogenic mechanisms such as Ca2+ dysregulation.
AGING CLINICAL AND EXPERIMENTAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Kyu-Hwan Shim, Min-Ju Kang, Heewon Bae, Danyeong Kim, Jiwon Park, Seong-Soo A. An, Da-Eun Jeong
Summary: A novel PSEN2 mutation was identified in a patient with early-onset Alzheimer's disease, which may promote the pathogenesis of the disease through altered phosphorylation of presenilin and APP processing. Further functional studies are needed to clarify the pathogenicity of the mutation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Geriatrics & Gerontology
Angeliki M. Nikolakopoulou, Anastasios Georgakopoulos, Nikolaos K. Robakis
NEUROBIOLOGY OF AGING
(2016)
Article
Geriatrics & Gerontology
Vincent Maingret, Gael Barthet, Severine Deforges, Nan Jiang, Christophe Mulle, Thierry Amedee
NEUROBIOLOGY OF AGING
(2017)
Article
Biochemistry & Molecular Biology
Noel A. Warren, Georgios Voloudakis, Yonejung Yoon, Nikolaos K. Robakis, Anastasios Georgakopoulos
CELLULAR AND MOLECULAR LIFE SCIENCES
(2018)
Article
Biochemistry & Molecular Biology
Qian Huang, Georgios Voloudakis, Yimin Ren, Yonejung Yoon, Emily Zhang, Yuji Kajiwara, Zhiping Shao, Zhao Xuan, Denis Lebedev, Anastasios Georgakopoulos, Nikolaos K. Robakis
Article
Multidisciplinary Sciences
Gael Barthet, Tomas Jorda-Siquier, Julie Rumi-Masante, Fanny Bernadou, Ulrike Mueller, Christophe Mulle
NATURE COMMUNICATIONS
(2018)
Article
Biochemical Research Methods
Hazal Haytural, Georgios Mermelekas, Ceren Emre, Saket Milind Nigam, Steven L. Carroll, Bengt Winblad, Nenad Bogdanovic, Gael Barthet, Ann-Charlotte Granholm, Lukas M. Orre, Lars O. Tjernberg, Susanne Frykman
MOLECULAR & CELLULAR PROTEOMICS
(2020)
Article
Geriatrics & Gerontology
Hazal Haytural, Jolanta L. Lundgren, Tansu B. Kose, Tomas Jorda-Siquier, Marinela Kalcheva, Mohammed Seed Ahmed, Bengt Winblad, Erik Sundstrom, Gael Barthet, Lars O. Tjernberg, Susanne Frykman
FRONTIERS IN AGING NEUROSCIENCE
(2019)
Review
Neurosciences
Gael Barthet, Christophe Mulle
PROGRESS IN NEUROBIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
YoneJung Yoon, Georgios Voloudakis, Nathan Doran, Emily Zhang, Christina Dimovasili, Lei Chen, Zhiping Shao, Spyros Darmanis, Cheuk Tang, Jun Tang, Victoria X. Wang, Patrick R. Hof, Nikolaos K. Robakis, Anastasios Georgakopoulos
Summary: The study reveals that PS1 FAD mutations impair the angiogenic functions of endothelial cells in the brain, leading to reduced neovascularization and decreased neuronal survival and cognitive recovery after ischemia. These effects occur independently of neuropathological hallmarks of AD, suggesting that they may play a role downstream of mutant effects on vascular growth and neural survival.
MOLECULAR PSYCHIATRY
(2021)
Article
Cell Biology
Benjamin J. A. Robert, Maite M. Moreau, Steve Dos Santos Carvalho, Gael Barthet, Claudia Racca, Mehdi Bhouri, Anne Quiedeville, Maurice Garret, Benedicte Atchama, Alice Shaam Al Abed, Christelle Guette, Deborah J. Henderson, Aline Desmedt, Christophe Mulle, Aline Marighetto, Mireille Montcouquiol, Nathalie Sans
Article
Clinical Neurology
Tomas Jorda-Siquier, Melina Petrel, Vladimir Kouskoff, Una Smailovic, Fabrice Cordelieres, Susanne Frykman, Ulrike Mueller, Christophe Mulle, Gael Barthet
Summary: The distribution of amyloid precursor protein (APP) and its fragments is altered in Alzheimer's disease (AD), leading to their accumulation around amyloid plaques with presynaptic proteins. This finding is associated with histopathological features and familial AD.
ALZHEIMERS & DEMENTIA
(2022)
Article
Neurosciences
Adam Gorlewicz, Gael Barthet, Stefano Zucca, Peggy Vincent, Marilena Griguoli, Noelle Grosjean, Grzegorz Wilczynski, Christophe Mulle
Summary: Kainate receptors (KARs) play a crucial role in regulating synaptic circuits through ionotropic or metabotropic mechanisms. This study reveals that the acute convulsive effect of kainate is primarily dependent on GluK2/GluK5 containing KARs, while the convulsive activity induced by pilocarpine and pentylenetetrazol is not affected by the absence of KARs. Interestingly, the genetic inactivation of GluK2 increases susceptibility to acute pilocarpine-induced seizures.
Article
Cell Biology
Minsuk Kwak, Kaden M. Southard, Woon Ryoung Kim, Annie Lin, Nam Hyeong Kim, Ramu Gopalappa, Hyun Jung Lee, Minji An, Seo Hyun Choi, Yunmin Jung, Kunwoo Noh, Justin Farlow, Anastasios Georgakopoulos, Nikolaos K. Robakis, Min K. Kang, Matthew L. Kutys, Daeha Seo, Hyongbum Henry Kim, Yong Ho Kim, Jinwoo Cheon, Zev J. Gartner, Young-wook Jun
Summary: Adherens junctions (AJs) play a crucial role in organizing proteolytic hotspots and microdomains for the processing of transmembrane proteins such as Notch. Membrane microdomains within AJs coordinate regulated intramembrane proteolysis (RIP), while those outside AJs mediate the engagement of Notch ligand-receptor interactions. This mechanism directs the differentiation of neural progenitor cells and regulates the proteolysis of other cell-surface receptors.
NATURE CELL BIOLOGY
(2022)
Article
Clinical Neurology
Hazal Haytural, Tomas Jorda-Siquier, Bengt Winblad, Christophe Mulle, Lars O. Tjernberg, Ann-Charlotte Granholm, Susanne Frykman, Gael Barthet
Summary: The study found reduced levels of several presynaptic proteins in Alzheimer's disease cases, specifically in the outer molecular layer of the dentate gyrus, with other hippocampal sub-fields unaffected. This highlights the distinctive vulnerability of the outer molecular layer of the dentate gyms and supports the notion of presynaptic failure in Alzheimer's disease.
BRAIN COMMUNICATIONS
(2021)
Article
Clinical Neurology
Md Al Rahim, Yonejung Yoon, Christina Dimovasili, Zhiping Shao, Qian Huang, Emily Zhang, Nebojsa Kezunovic, Lei Chen, Adam Schaffner, George W. Huntley, Iban Ubarretxena-Belandia, Anastasios Georgakopoulos, Nikolaos K. Robakis
BRAIN COMMUNICATIONS
(2020)