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Johanna Jakobsdottir, Sven J van der Lee, Joshua C Bis, Vincent Chouraki, David Li-Kroeger, Shinya Yamamoto, Megan L Grove, Adam Naj, Maria Vronskaya, Jose L Salazar, Anita L DeStefano, Jennifer A Brody, Albert V Smith, Najaf Amin, Rebecca Sims, Carla A Ibrahim-Verbaas, Seung-Hoan Choi, Claudia L Satizabal, Oscar L Lopez, Alexa Beiser, M Arfan Ikram, Melissa E Garcia, Caroline Hayward, Tibor V Varga, Samuli Ripatti, Paul W Franks, Göran Hallmans, Olov Rolandsson, Jan-Håkon Jansson, David J Porteous, Veikko Salomaa, Gudny Eiriksdottir, Kenneth M Rice, Hugo J Bellen, Daniel Levy, Andre G Uitterlinden, Valur Emilsson, Jerome I Rotter, Thor Aspelund, Christopher J O'Donnell, Annette L Fitzpatrick, Lenore J Launer, Albert Hofman, Li-San Wang, Julie Williams, Gerard D Schellenberg, Eric Boerwinkle, Bruce M Psaty, Sudha Seshadri, Joshua M Shulman, Vilmundur Gudnason, Cornelia M van Duijn
We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling...
October 2016: PLoS Genetics
Xue-Yuan Li, Wei-Wei Men, Hua Zhu, Jian-Feng Lei, Fu-Xing Zuo, Zhan-Jing Wang, Zhao-Hui Zhu, Xin-Jie Bao, Ren-Zhi Wang
Alzheimer's disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using (18)F-labed fluorodeoxyglucose ((18)F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr)...
October 18, 2016: International Journal of Molecular Sciences
Laura Borrello, Chiara Cupidi, Valentina Laganà, Maria Anfossi, Maria Elena Conidi, Nicoletta Smirne, Maria Taverniti, Roberto Guarasci, Amalia Cecilia Bruni
The rebuilding of the N family, a large Italian kindred affected by early-onset autosomal dominant Alzheimer's disease (AD), provided an important contribution to the discovery of Presenilin 1 (PSEN1), the main gene responsible for familial AD. This pedigree was identified with the help of medical records from the archives of the Psychiatric Hospital of Girifalco, Italy. The clinical record of Angela R., an ancestor of the N family, dating back to 1904, showed a clinical picture of Angela R., consistent with a diagnosis of non-amnestic probable AD, matching the "dysexecutive" phenotype described in her descendants...
October 11, 2016: Journal of Neurology
M Rodríguez-Arribas, S M S Yakhine-Diop, J M Bravo-San Pedro, P Gómez-Suaga, R Gómez-Sánchez, G Martínez-Chacón, J M Fuentes, R A González-Polo, M Niso-Santano
Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i...
October 6, 2016: Molecular Neurobiology
Marzena Ułamek-Kozioł, Ryszard Pluta, Sławomir Januszewski, Janusz Kocki, Anna Bogucka-Kocka, Stanisław J Czuczwar
We review the Alzheimer-related expression of genes following brain ischemia as risk factors for late-onset of sporadic Alzheimer's disease and their role in Alzheimer's disease ischemia-reperfusion pathogenesis. More recent advances in understanding ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer-associated genes including amyloid protein precursor, β-secretase, presenilin 1 and 2, autophagy, mitophagy and apoptosis. We review the relationship between these genes dysregulated by brain ischemia and the cellular and neuropathological characteristics of Alzheimer's disease...
September 5, 2016: Pharmacological Reports: PR
Aitana Sogorb-Esteve, María-Salud García-Ayllón, Juan Fortea, Raquel Sánchez-Valle, Alberto Lleó, José-Luis Molinuevo, Javier Sáez-Valero
BACKGROUND: Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer's disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers. METHODS: Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes...
September 29, 2016: Molecular Neurodegeneration
Sha Liu, Shuang-Qi Tang, Heng-Jing Cui, Sha Yin, Ming Yin, Hong Zhao, Ling-Hua Meng, Ze-Jian Wang, Yang Lu
Recently, anandamide (AEA) analogues have been well recognized for its potent neuroprotective effects in counteracting the deterioration of Alzheimer's disease (AD) brains through multiple pathological processes. In our previous studies, dipotassium N-stearoyltyrosinate (NSTK), an AEA analogue synthesized by our laboratory was reported to exert significant efficacy through multiple interventions. Within this study, the amyloid precursor protein (APP)SWE/presenilin-1 (PS1)M146V/TauP301L mouse (3×Tg-AD) model was used to explore further the neuroprotective effects of NSTK and its underlying mechanisms...
September 2016: Journal of Pharmacological Sciences
Muhammad Zahid Khan, Nagina Atlas, Waqas Nawaz
Cognitive deficiency and oxidative stress have been well documented in aging disorders including Alzheimer's disease. The aim of this study was to investigate the therapeutic efficacy of Caralluma tuberculata methanolic extract (CTME) on cognitive impairment in mice induced with d-galactose. In this study we assessed the therapeutic efficacy of CTME on cognitive impairment in mice induced with d-galactose by conduction of behavioral and cognitive performance tests. In order to explore the possible role of CTME against d-galactose-induced oxidative damages, various biochemical indicators were assessed...
September 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Joanna Wojsiat, Katarzyna Laskowska-Kaszub, Carolina Alquézar, Emilia Białopiotrowicz, Noemi Esteras, Mykola Zdioruk, Angeles Martin-Requero, Urszula Wojda
Familial (FAD) and sporadic (SAD) Alzheimer's disease do not share all pathomechanisms, but knowledge on their molecular differences is limited. We previously reported that cell cycle control distinguishes lymphocytes from SAD and FAD patients. Significant differences were found in p21 levels of SAD compared to FAD lymphocytes. Since p21 can also regulate apoptosis, the aim of this study was to compare the response of FAD and SAD lymphocytes to oxidative stress like 2-deoxy-D-ribose (2dRib) treatment and to investigate the role of p21 levels in this response...
September 19, 2016: Molecular Neurobiology
Elena Popugaeva, Ekaterina Pchitskaya, Ilya Bezprozvanny
Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca(2+)) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca(2+) signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca(2+) leak function of presenilins. Excessive ER Ca(2+) release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2...
September 15, 2016: Biochemical and Biophysical Research Communications
Tohru Hasegawa, Wataru Ukai
At present, we have no reliable means of recovering cognitive impairment in Alzheimer's disease (AD) patients. We hypothesized that homocysteic acid (HA) in the blood might represent one such pathogen that could be excreted into the urine. Since DHA is known to reduce circulating levels of homocysteine, and since exercise attenuates this effect, it follows that supplementation of the diet with DHA, along with increased levels of physical activity, may help to reduce cognitive impairment in AD patients. Our hypothesis was proven to be correct because memory problems in 3xTg- AD mice (a model for AD in which animals develop amyloid pathology), and in a mouse model of familial AD, were recovered following treatment with an anti-HA antibody and not by amyloid treatment...
September 14, 2016: Aging
Tian Tian, Dong Bai, Wen Li, Guo-Wei Huang, Huan Liu
Alzheimer's disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase...
2016: Nutrients
Steffan K Soosman, Nelly Joseph-Mathurin, Meredith N Braskie, Yvette M Bordelon, David Wharton, Maria Casado, Giovanni Coppola, Holly McCallum, Marc Nuwer, Pedro Coutin-Churchman, Liana G Apostolova, Tammie Benzinger, John M Ringman
The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP...
August 8, 2016: Neurobiology of Aging
Yoji Yonemura, Eugene Futai, Sosuke Yagishita, Christoph Kaether, Shoichi Ishiura
The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2). PS has two homologues, PS1 and PS2. Aph1 has two isoforms, Aph1a and Aph1b, with the former existing as two splice variants Aph1aL and Aph1aS. Each complex consists of one subunit each, resulting in six different γ-secretases. To better understand the functional differences among the γ-secretases, we reconstituted them using a yeast system and compared Notch1-cleavage and amyloid precursor protein (APP)-cleavage activities...
September 30, 2016: Biochemical and Biophysical Research Communications
Benjamin Chun-Kit Tong, Claire Shuk-Kwan Lee, Wing-Hei Cheng, Kwok-On Lai, J Kevin Foskett, King-Ho Cheung
Some forms of familial Alzheimer's disease (FAD) are caused by mutations in presenilins (PSs), catalytic components of a γ-secretase complex that cleaves target proteins, including amyloid precursor protein (APP). Calcium (Ca(2+)) dysregulation in cells with these FAD-causing PS mutants has been attributed to attenuated store-operated Ca(2+) entry [SOCE; also called capacitative Ca(2+) entry (CCE)]. CCE occurs when STIM1 detects decreases in Ca(2+) in the endoplasmic reticulum (ER) and activates ORAI channels to replenish Ca(2+) stores in the ER...
2016: Science Signaling
Saak Victor Ovsepian, Lidia Blazquez-Llorca, Susana Valero Freitag, Eva Ferreira Rodrigues, Jochen Herms
Synaptic dysfunctions and altered neuronal activity play major role in the pathophysiology of Alzheimer's disease (AD), with underlying mechanisms largely unknown. We report that in the prefrontal cortex of amyloid precursor protein-presenilin 1 and APP23 AD mice, baseline activity of pyramidal cells is disrupted by episodes of paroxysmal hyperactivity. Induced by spontaneous EPSC bursts, these incidents are prevalent in neurons proximal to amyloid plaques and involve enhanced activity of glutamate with metabotropic effects...
September 6, 2016: Cerebral Cortex
Elisa Greotti, Andrea Wong, Tullio Pozzan, Diana Pendin, Paola Pizzo
Calcium ion (Ca(2+)) is a ubiquitous intracellular messenger and changes in its concentration impact on nearly every aspect of cell life. Endoplasmic reticulum (ER) represents the major intracellular Ca(2+) store and the free Ca(2+) concentration ([Ca(2+)]) within its lumen ([Ca(2+)]ER) can reach levels higher than 1 mM. Several genetically-encoded ER-targeted Ca(2+) sensors have been developed over the last years. However, most of them are non-ratiometric and, thus, their signal is difficult to calibrate in live cells and is affected by shifts in the focal plane and artifactual movements of the sample...
2016: Sensors
Qingwang Lian, Yongsheng Nie, Xiaoyou Zhang, Bo Tan, Hongying Cao, Wenling Chen, Weiming Gao, Jiayi Chen, Zhijian Liang, Huangling Lai, Siming Huang, Yifei Xu, Weiwen Jiang, Ping Huang
Grape seed proanthocyanidin (GSPA) consists of catechin, epicatechin and epicatechin gallate, which are strong antioxidants that are beneficial to health and may attenuate or prevent Alzheimer's disease (AD). In the present study, the effects of GSPA on pheochromocytoma (PC12) cell viability were determined using cell counting kit-8 and lactate dehydrogenase (LDH) assays, whereas apoptosis and mitochondrial membrane potential (Ψm) were measured via flow cytometry analysis. The effect of GSPA administration on the behavior and memory of amyloid precursor protein (APP)/presenilin-1 (PS-1) double transgenic mice was assessed using a Morris water maze...
September 2016: Experimental and Therapeutic Medicine
Arnaldo Parra-Damas, Meng Chen, Lilian Enriquez-Barreto, Laura Ortega, Sara Acosta, Judith Camats Perna, M Neus Fullana, José Aguilera, José Rodríguez-Alvarez, Carlos A Saura
BACKGROUND: Associative memory impairment is an early clinical feature of dementia patients, but the molecular and cellular mechanisms underlying these deficits are largely unknown. In this study, we investigated the functional regulation of the cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) by associative learning in physiological and neurodegenerative conditions. METHODS: We evaluated the activation of CRTC1 in the hippocampus of control mice and mice lacking the Alzheimer's disease-linked presenilin genes (presenilin conditional double knockout [PS cDKO]) after one-trial contextual fear conditioning by using biochemical, immunohistochemical, and gene expression analyses...
July 11, 2016: Biological Psychiatry
Jean-François Blain, Matthew G Bursavich, Emily A Freeman, Lori A Hrdlicka, Hilliary E Hodgdon, Ting Chen, Don E Costa, Bryce A Harrison, Sudarshan Kapadnis, Deirdre A Murphy, Scott Nolan, Zhiming Tu, Cuyue Tang, Duane A Burnett, Holger Patzke, Gerhard Koenig
BACKGROUND: Familial Alzheimer's disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for the majority of FAD cases, lead to an increased ratio of longer to shorter forms of the amyloid beta (Aβ) peptide. The therapeutic rationale of γ-secretase modulators (GSMs) for Alzheimer's disease is based on this genetic evidence as well as on enzyme kinetics measurements showing changes in the processivity of the γ-secretase complex...
2016: Alzheimer's Research & Therapy
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