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Alzheimers and cholesterol

Hee Kim Dong, Jeong-An Gim, Seung Hyeon Yeo, Heui-Soo Kim
Late onset Alzheimer's disease (LOAD) is the most common type of dementia and is characterized by decreased amyloid-β (Aβ) clearance from the brain. Cholesterol regulates the production and clearance of Aβ. Genome-wide association study (GWAS) suggests that at least 20 genes are associated with LOAD. The genes APOE, CLU, SORL1, PICALM, and BIN1 have a relatively high LOAD susceptibility. Additional experimental and bioinformatic approaches to integrate data from genetics, epigenetics, and molecular networks may further increase our understanding of LOAD in relation to cholesterol metabolism and trafficking...
October 20, 2016: Gene
Raquel Marin, Noemí Fabelo, Virginia Martín, Paula Garcia-Esparcia, Isidre Ferrer, David Quinto-Alemany, Mario Díaz
Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occur in other types of dementia such dementia with Lewy bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n-3 long-chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes...
September 6, 2016: Neurobiology of Aging
Zhiyou Cai, Chuanling Wang, Wenming Yang
Berberine, an important protoberberine isoquinoline alkaloid, has several pharmacological activities, including antimicrobial, glucose- and cholesterol-lowering, antitumoral, and immunomodulatory properties. Substantial studies suggest that berberine may be beneficial to Alzheimer's disease (AD) by limiting the pathogenesis of extracellular amyloid plaques and intracellular neurofibrillary tangles. Increasing evidence has indicated that berberine exerts a protective role in atherosclerosis related to lipid- and glucose-lowering properties, implicating that berberine has the potential to inhibit these risk factors for AD...
2016: Neuropsychiatric Disease and Treatment
E Candeias, A I Duarte, I Sebastião, M A Fernandes, A I Plácido, C Carvalho, S Correia, R X Santos, R Seiça, M S Santos, C R Oliveira, P I Moreira
Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e...
October 11, 2016: Molecular Neurobiology
Frank J Wolters, Francesco U S Mattace-Raso, Peter J Koudstaal, Albert Hofman, M Arfan Ikram
BACKGROUND: Orthostatic hypotension (OH) is a common cause of transient cerebral hypoperfusion in the population. Cerebral hypoperfusion is widely implicated in cognitive impairment, but whether OH contributes to cognitive decline and dementia is uncertain. We aimed to determine the association between OH and the risk of developing dementia in the general population. METHODS AND FINDINGS: Between 4 October 1989 and 17 June 1993, we assessed OH in non-demented, stroke-free participants of the population-based Rotterdam Study...
October 2016: PLoS Medicine
Gabriella Testa, Erica Staurenghi, Chiara Zerbinati, Simona Gargiulo, Luigi Iuliano, Giorgio Giaccone, Fausto Fantò, Giuseppe Poli, Gabriella Leonarduzzi, Paola Gamba
Alzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD...
September 16, 2016: Redox Biology
Juho Tynkkynen, Jussi A Hernesniemi, Tiina Laatikainen, Aki S Havulinna, Jouko Sundvall, Jaana Leiviskä, Perttu Salo, Veikko Salomaa
Data on associations of apolipoproteins A-I and B (apo A-I, apo B) and HDL cholesterol (HDL-C) with dementia and Alzheimer's disease (AD) are conflicting. Our aim was to examine, whether apo B, apoA-I, their ratio, or HDL-C are significant, independent predictors of incident dementia and AD in the general population free of dementia at baseline. We analyzed the results from two Finnish prospective population-based cohort studies in a total of 13,275 subjects aged 25 to 74 years with mainly Caucasian ethnicity...
September 23, 2016: Age (2005-)
Francesca Zimetti, Paolo Caffarra, Nicoletta Ronda, Elda Favari, Maria Pia Adorni, Ilaria Zanotti, Franco Bernini, Federica Barocco, Marco Spallazzi, Daniela Galimberti, Chiara Ricci, Massimiliano Ruscica, Alberto Corsini, Nicola Ferri
BACKGROUND: Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. OBJECTIVE: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4...
September 20, 2016: Journal of Alzheimer's Disease: JAD
Burcu F Darst, Rebecca L Koscik, Annie M Racine, Jennifer M Oh, Rachel A Krause, Cynthia M Carlsson, Henrik Zetterberg, Kaj Blennow, Bradley T Christian, Barbara B Bendlin, Ozioma C Okonkwo, Kirk J Hogan, Bruce P Hermann, Mark A Sager, Sanjay Asthana, Sterling C Johnson, Corinne D Engelman
Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response...
September 21, 2016: Journal of Alzheimer's Disease: JAD
Inci Kazkayasi, Muhammad-Al-Mustafa Ismail, Cristina Parrado-Fernandez, Ingemar Björkhem, Can Pekiner, Serdar Uma, Angel Cedazo-Minguez, Nihan Burul-Bozkurt
Several studies demonstrated that Diabetes mellitus (DM) enhances the risk for Alzheimer's disease (AD). Although hyperglycemia and perturbed function of insulin signaling have been proposed to contribute to AD pathogenesis, the molecular mechanisms behind this association is not clear yet. Seladin-1 is an enzyme catalyzing the last step in cholesterol biosynthesis converting desmosterol to cholesterol. The neuroprotective function of seladin-1 has gained interest in AD research recently. Seladin-1 has anti-apoptotic properties and regulates the expression of β-secretase (BACE-1)...
October 28, 2016: Neuroscience Letters
Anne M Brown, David R Bevan
The aggregation cascade and peptide-membrane interactions of the amyloid β-peptide (Aβ) have been implicated as toxic events in the development and progression of Alzheimer's disease. Aβ42 forms oligomers and ultimately plaques, and it has been hypothesized that these oligomeric species are the main toxic species contributing to neuronal cell death. To better understand oligomerization events and subsequent oligomer-membrane interactions of Aβ42, we performed atomistic molecular-dynamics (MD) simulations to characterize both interpeptide interactions and perturbation of model membranes by the peptides...
September 6, 2016: Biophysical Journal
Marija Macesic, Nebojsa M Lalic, Vladimir S Kostic, Aleksandra Jotic, Katarina Lalic, Elka Stefanova, Tanja Milicic, Ljiljana Lukic, Jelena Stanarcic Gajovic, Nina Krako
OBJECTIVE: We analysed: (a) insulin sensitivity, (b) insulin secretion capacity, (c) plasma insulin, (d) adiponectin levels, and, (e) lipid parameters in normoglycaemic, nonobese patients with Alzheimer's disease (AD) (group A, n=62), mild cognitive impairment (MCI) (group B, n=41), and healthy controls (group C, n=25). METHOD: Insulin sensitivity was determined both by euglycemic hyperinsulinaemic clamp (M value) and homeostasis model assessment (HOMA-IR), insulin secretion capacity by acute insulin response and first-phase insulin response (FPIR), plasma insulin by RIA and adiponectin by ELISA methods, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides by enzymatic method...
September 5, 2016: Current Vascular Pharmacology
Jianjia Fan, Shahab Zareyan, Wenchen Zhao, Yoko Shimizu, Tom A Pfeifer, Jun-Hyung Tak, Murray B Isman, Bernard Van den Hoven, Mark E Duggan, Michael W Wood, Cheryl L Wellington, Iva Kulic
The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media...
2016: PloS One
Qingying Zhang, Yan Cheng, Mulan He, Tingting Li, Ziwen Ma, Haidong Cheng
It has previously been reported that the influence of vitamin D on the metabolism of calcium and phosphorus is associated with diabetes, cardiovascular disease, Alzheimer's disease, cancer and other systemic diseases, and is considered an important indicator of general health. The present study was conducted to determine the effect of various doses of vitamin D supplementation on glucose metabolism, lipid concentrations, inflammation and the levels of oxidative stress of pregnant women with gestational diabetes mellitus (GDM)...
September 2016: Experimental and Therapeutic Medicine
M J Yáñez, O Belbin, L D Estrada, N Leal, P S Contreras, A Lleó, P V Burgos, S Zanlungo, A R Alvarez
BACKGROUND: Niemann-Pick type C (NPC) disease is characterized by lysosomal accumulation of cholesterol. Interestingly, NPC patients' brains also show increased levels of amyloid-β (Aβ) peptide, a key protein in Alzheimer's disease pathogenesis. We previously reported that the c-Abl tyrosine kinase is active in NPC neurons and in AD animal models and that Imatinib, a specific c-Abl inhibitor, decreased the amyloid burden in brains of the AD mouse model. Active c-Abl was shown to interact with the APP cytosolic domain, but the relevance of this interaction to APP processing has yet to be defined...
August 23, 2016: Biochimica et Biophysica Acta
Maud Gratuze, Jacinthe Julien, Françoise Morin, Frédéric Calon, Sébastien S Hébert, André Marette, Emmanuel Planel
Aggregates of hyperphosphorylated tau protein are a pathological hallmark of Alzheimer's disease (AD). The origin of AD is multifactorial, and many metabolic disorders originating from overconsumption of fat, cholesterol, and sugar are associated with higher risk of AD later in life. However, the effects of fat, cholesterol, and sugar overconsumption on tau pathology in AD remain controversial. Using the hTau mice, a model of AD-like tau pathology, we assessed the effects of high-fat, high-cholesterol, and/or high-sugar diets on tau pathogenesis...
July 29, 2016: Neurobiology of Aging
Pia Elustondo, Laura A Martin, Barbara Karten
All animal subcellular membranes require cholesterol, which influences membrane fluidity and permeability, fission and fusion processes, and membrane protein function. The distribution of cholesterol among subcellular membranes is highly heterogeneous and the cholesterol content of each membrane must be carefully regulated. Compared to other subcellular membranes, mitochondrial membranes are cholesterol-poor, particularly the inner mitochondrial membrane (IMM). As a result, steroidogenesis can be controlled through the delivery of cholesterol to the IMM, where it is converted to pregnenolone...
August 23, 2016: Biochimica et Biophysica Acta
Martina Audagnotto, Thomas Lemmin, Alessandro Barducci, Matteo Dal Peraro
The proteolytic cleavage of the transmembrane (TM) domain of the amyloid precursor protein (APP) releases amyloid-β (Aβ) peptides, which accumulation in the brain tissue is an early indicator of Alzheimer's disease. We used multiscale molecular dynamics simulations to investigate the stability of APP-TM dimer in realistic models of the synaptic plasma membrane (SPM). Between the two possible dimerization motifs proposed by NMR and EPR, namely G709XXXA713 and G700XXXG704XXXG708, our study revealed that the dimer promoted by the G709XXXA713 motif is not stable in the SPM due to the competition with highly unsaturated lipids that constitute the SPM...
September 15, 2016: Journal of Physical Chemistry Letters
Rongrong Cai, Jing Han, Jie Sun, Rong Huang, Sai Tian, Yanjue Shen, Xue Dong, Wenqing Xia, Shaohua Wang
OBJECTIVE: Type 2 diabetes mellitus (T2DM) is related to an elevated risk of mild cognitive impairment (MCI). Plasma clusterin is reported associated with the early pathology of Alzheimer's disease (AD) and longitudinal brain atrophy in subjects with MCI. The rs11136000 single nucleotide polymorphism within the clusterin (CLU) gene is also associated with the risk of AD. We aimed to investigate the associations among plasma clusterin, rs11136000 genotype and T2DM-associated MCI. METHODS: A total of 231 T2DM patients, including 126 MCI and 105 cognitively healthy controls were enrolled in this study...
2016: Frontiers in Aging Neuroscience
Nicolette Mary Heinsinger, Mariam Alexandra Gachechiladze, G William Rebeck
Apolipoprotein E (apoE) is associated with lipoproteins in the cerebrospinal fluid (CSF). APOE4 increases and APOE2 decreases the risk for Alzheimer disease (AD) compared to the risk associated with APOE3 Because apoE4 is less efficient at cholesterol efflux than apoE2 or apoE3 in vitro, we hypothesized that APOE genotype may affect apoE particle size in vivo and that these size differences may be related to AD risk. We used nondenaturing gel electrophoresis to test for differences in the size of apoE complexes in human CSF samples of various APOE genotypes and created profiles of each sample to compare the patterns of apoE distribution...
August 11, 2016: Journal of Neuropathology and Experimental Neurology
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