scholarly journals Protection against APOE4-associated aging phenotypes with a longevity-promoting intervention

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 957-957
Author(s):  
Cassandra McGill ◽  
Amy Christensen ◽  
Wenjie Qian ◽  
Caleb Finch ◽  
Berenice Benayoun ◽  
...  
Keyword(s):  
Late Onset ◽  
Frailty Index ◽  
Intervention Strategy ◽  
Apoe Genotype ◽  
Metabolic Phenotype ◽  
Neural Pathways ◽  
Senescent Phenotype ◽  
Specific Effects ◽  
Normal Chow ◽  
Plasma Leptin

Abstract Two of the primary risk factors for late onset Alzheimer’s Disease (AD) are aging and APOE genotype. While the causal relationship between aging and AD is not well defined, there are strong leads from shared phenotypes such as decreased metabolic function and increased inflammation. APOE genotype may be linked to AD phenotypes through the regulation of aging processes. The NIA Interventions Testing Program (ITP) recently found that 17α-estradiol (17αE2) treatment increases rodent lifespan. Since 17αE2 acts upon systemic and neural pathways associated with AD pathology, we propose that 17αE2 may be a pleiotropic intervention strategy. Further, because APOE4 is associated with a senescent phenotype, 17αE2 may have APOE genotype-specific effects. Using 10-month-old APOE3 or APOE4 targeted replacement male mice maintained on normal chow with and without 14.4 ppm 17aE2 for 20 weeks, our initial results indicate genotype differences in the efficacy of 17αE2 across multiple outcomes. APOE4 mice exhibited an aged phenotype compared to APOE3, with APOE4 mice having a higher frailty index; however, 17αE2 treatment reduced the frailty index most strongly in APOE4 mice. APOE4 mice were impaired across multiple metabolic measures including body weight, plasma leptin, and hepatic steatosis. 17αE2 significantly attenuated the APOE4 metabolic phenotype. These data confirm and extend prior findings that APOE4 is linked to progeroid effects both peripheral and neural outcomes associated with AD risk. Importantly, 17αE2 significantly improved a range of measures, but showed the strongest effects in the APOE4 genotype. This research was funded by the Cure Alzheimer's Fund.

Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021 ◽  
pp. 1-10
Author(s):  
Wei Qin ◽  
Wenwen Li ◽  
Qi Wang ◽  
Min Gong ◽  
Tingting Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Black People ◽  
Late Onset ◽  
Meta Analysis ◽  
Group Analysis ◽  
Apoe Genotype ◽  
Cochrane Library ◽  
Data Sets ◽  
Apoe Genotypes

Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ɛ4 was a risk factor for AD, whereas APOE ɛ2 protected against it. The effects of APOE ɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ɛ4/ɛ4 and lower frequency of APOE ɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

Vitamin D Levels, APOE Allele, and MRI Volumetry Assessed by NeuroQuant in Norwegian Adults with Cognitive Symptoms

2021 ◽  
Vol 79 (1) ◽  
pp. 311-321
Author(s):  
Jelena Zugic Soares ◽  
Renate Pettersen ◽  
Jūratė Šaltytė Benth ◽  
Karin Persson ◽  
Carsten Strobel ◽  
...  
Keyword(s):  
Vitamin D ◽  
Late Onset ◽  
Apoe Genotype ◽  
Serum Levels ◽  
Grey Matter Volume ◽  
Cognitive Symptoms ◽  
Cross Sectional ◽  
Brain Volumes ◽  
Vitamin D Levels ◽  
Mri Volumetry

Background: Allele ɛ4 of the apolipoprotein (APOE ∈4) gene is the strongest known genetic risk factor for late-onset sporadic Alzheimer’s disease. A possible relationship between vitamin D and APOE is not yet clear. Objective: In this exploratory, cross-sectional study, we examined the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and brain volumes and the associations of both serum levels of 25(OH)D and APOE polymorphism to brain volumes in 127 persons (mean age 66 years) with cognitive symptoms. Methods: All subjects were examined with fully automated software for MRI volumetry, NeuroQuant. Results: After adjustment for relevant covariates, higher serum 25(OH)D levels were associated with greater volumes of cortical gray matter on both left (p = 0.02) and right (p = 0.04) sides. When both 25(OH)D levels and APOE genotype were used as the main covariates, no significant associations were found between vitamin D level and brain volume in any of the 11 brain regions. In adjusted models, only homozygous but not heterozygous APOE ∈4 allele carriers had significantly larger inferior lateral ventricles (p = 0.003) and smaller hippocampal volume (p = 0.035) than those without ɛ4. Homozygous APOE ∈4 carriers also had significantly higher vitamin D levels (p = 0.009) compared to persons without the APOE ∈4 allele. Conclusion: Higher vitamin D levels might have a preserving effect on cortical grey matter volume.

scholarly journals The effect of calorie intake, fasting, and dietary composition on metabolic health and gut microbiota in mice

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ziyi Zhang ◽  
Xiaoyu Chen ◽  
Yuh Jiun Loh ◽  
Xin Yang ◽  
Chenhong Zhang
Keyword(s):  
Gut Microbiota ◽  
High Fat Diet ◽  
Metabolic Health ◽  
Metabolic Phenotype ◽  
Intermittent Fasting ◽  
High Fat ◽  
Eating Pattern ◽  
Positive Effects ◽  
Normal Chow ◽  
Ad Libitum

Abstract Background Calorie restriction (CR) and intermittent fasting (IF) can promote metabolic health through a process that is partially mediated by gut microbiota modulation. To compare the effects of CR and IF with different dietary structures on metabolic health and the gut microbiota, we performed an experiment in which mice were subjected to a CR or IF regimen and an additional IF control (IFCtrl) group whose total energy intake was not different from that of the CR group was included. Each regimen was included for normal chow and high-fat diet. Results We showed that in normal-chow mice, the IFCtrl regimen had similar positive effects on glucose and lipid metabolism as the CR regimen, but the IF regimen showed almost no influence compared to the outcomes observed in the ad libitum group. IF also resulted in improvements, but the effects were less marked than those associate with CR and IFCtrl when the mice were fed a high-fat diet. Moreover, CR created a stable and unique gut microbial community, while the gut microbiota shaped by IF exhibited dynamic changes in fasting-refeeding cycles. At the end of each cycle, the gut microbiota of the IFCtrl mice was similar to that of the CR mice, and the gut microbiota of the IF mice was similar to that of the ad libitum group. When the abundance of Lactobacillus murinus OTU2 was high, the corresponding metabolic phenotype was improved regardless of eating pattern and dietary structure, which might be one of the key bacterial groups in the gut microbiota that is positively correlated with metabolic amelioration. Conclusion There are interactions among the amount of food intake, the diet structure, and the fasting time on metabolic health. The structure and composition of gut microbiota modified by dietary regimens might contribute to the beneficial effects on the host metabolism.

scholarly journals Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats

2000 ◽  
Vol 278 (4) ◽  
pp. E677-E683 ◽  
Author(s):  
Asako Suga ◽  
Tsutomu Hirano ◽  
Haruaki Kageyama ◽  
Toshimasa Osaka ◽  
Yoshio Namba ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Body Weight Gain ◽  
Intravenous Glucose Tolerance Test ◽  
Fat Pad ◽  
Intravenous Glucose ◽  
Dietary Fructose ◽  
Obese Rats ◽  
Normal Chow ◽  
Plasma Leptin

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.

scholarly journals Influence of brain-derived neurotrophic factor and apolipoprotein E genetic variants on hemispheric and lateral ventricular volume of young healthy adults

2011 ◽  
Vol 23 (3) ◽  
pp. 132-138 ◽  
Author(s):  
Christos Sidiropoulos ◽  
Kourosh Jafari-Khouzani ◽  
Hamid Soltanian-Zadeh ◽  
Panayiotis Mitsias ◽  
Panagiotis Alexopoulos ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Neurotrophic Factor ◽  
Late Onset ◽  
Apoe Genotype ◽  
Ventricular Volume ◽  
Brain Derived Neurotrophic Factor ◽  
Healthy Adults ◽  
Ventricular Volumes ◽  
Neuronal Processes ◽  
Apoe Genotypes

Objective: Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) are thought to be implicated in a variety of neuronal processes, including cell growth, resilience to noxious stimuli and synaptic plasticity. A Val to Met substitution at codon 66 in the BDNF protein has been associated with a variety of neuropsychiatric conditions. The ApoE4 allele is considered a risk factor for late-onset Alzheimer's disease, but its effects on young adults are less clear. We sought to investigate the effects of those two polymorphisms on hemispheric and lateral ventricular volumes of young healthy adults.Methods: Hemispheric and lateral ventricular volumes of 144 healthy individuals, aged 19–35 years, were measured using high resolution magnetic resonance imaging and data were correlated with BDNF and ApoE genotypes.Results: There were no correlations between BDNF or ApoE genotype and hemispheric or lateral ventricular volumes.Conclusion: These findings indicate that it is unlikely that either the BDNF Val66Met or ApoE polymorphisms exert any significant effect on hemispheric or lateral ventricular volume. However, confounding epistatic genetic effects as well as relative insensitivity of the volumetric methods used cannot be ruled out. Further imaging analyses are warranted to better define any genetic influence of the BDNF Val6Met and ApoE polymorphism on brain structure of young healthy adults.

scholarly journals Late Onset Alzheimer Dementia in Patients with Genotype E3/E4: A Case Report

2021 ◽  
Vol 9 (C) ◽  
pp. 5-9
Author(s):  
Anak Agung Ayu Putri Laksmidewi ◽  
Chiquita Putri Vania Rau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Case Report ◽  
Mini Mental State Examination ◽  
Late Onset ◽  
Apoe Genotype ◽  
Time Orientation ◽  
Alzheimer Dementia ◽  
The Family ◽  
State Examination

BACKGROUND: Dementia is one of the leading causes of disability and dependence in elderly worldwide. Epidemiological statistics indicate that data show that at about 60–80%, Alzheimer’s is the most common type of dementia. Alzheimer’s is also the third-most prominent cause of death in elderly. CASE REPORT: A 72-years-old male patient, complained by the family often forgets about things that have just been done for 3 years ago. According to the family, patient also often discussing the same things repeatedly. Patients tend not to have the initiative to start his daily activities. The family admitted that patient also became often angry and felt suspicious for the last 2 years. From the mini mental state examination showed disturbances in time orientation and recall; from Montreal Cognitive Assessment Ina found disturbances in visuospatial, fluency, abstraction, delayed memory, and time orientation; accompanied by activities of daily living (ADL) and instrumental ADL disorders. Patient also performed a molecular examination of the apolipoprotein E (APOE) genotype and the genotype E3/E4 was detected. CONCLUSION: The function of the APOE gene, in particular APOE4, is the most emphasized genetic relationship in late onset Alzheimer’s disease. It is proposed that blocking the action of APOE4 can delay or stop Alzheimer’s disease progression.

Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity

2004 ◽  
Vol 286 (6) ◽  
pp. E891-E895 ◽  
Author(s):  
Kamal Rahmouni ◽  
Allyn L. Mark ◽  
William G. Haynes ◽  
Curt D. Sigmund
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Rnase Protection Assay ◽  
Regulatory Sequences ◽  
High Fat ◽  
Rnase Protection ◽  
Brown Adipose ◽  
Normal Chow ◽  
Plasma Leptin

Adipose tissue represents an important source of angiotensinogen (AGT). We investigated the effect of obesity induced by a high-fat diet on the expression of mouse (mAGT) and human AGT (hAGT) genes in liver, kidney, and heart and different adipose depots in normal mice (C57BL/6J), and in transgenic mice expressing the hAGT gene under the control of its own promoter. Mice were fed a high-fat diet (45% kcal) or normal chow (10% kcal) for 10 and 20 wk. The expression of mAGT and hAGT mRNA was quantified using an RNAse protection assay. Mice on the high-fat diet exhibited increased weight, fat mass, and plasma leptin. Expression of mAGT or hAGT genes was not affected by high-fat diet in nonadipose tissues, brown adipose tissue, or subcutaneous white fat. In contrast, high-fat diet increased both mAGT and hAGT gene expression in visceral adipose depots (omental, reproductive, and perirenal fat). Thus obesity-induced by a high-fat diet is associated with a tissue-specific increased expression of both mouse and human AGT genes in intra-abdominal adipose tissue. Our findings also suggest that 1.2 kb of regulatory sequences present in the hAGT transgene are sufficient to transcriptionally respond to a high-fat diet in an adipose-specific and depot-specific manner.

scholarly journals Altered Proteolysis in Fibroblasts of Alzheimer Patients with Predictive Implications for Subjects at Risk of Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Alessandra Mocali ◽  
Nunzia Della Malva ◽  
Claudia Abete ◽  
Vito Antonio Mitidieri Costanza ◽  
Antonio Bavazzano ◽  
...  
Keyword(s):  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Low Cost ◽  
Apoe Genotype ◽  
Normal Subjects ◽  
Culture Conditions ◽  
Cultured Fibroblasts ◽  
Laboratory Tool

There is great interest in developing reliable biomarkers to support antemortem diagnosis of late-onset Alzheimer’s disease (AD). Early prediction and diagnosis of AD might be improved by the detection of a proteolytic dysfunction in extracts from cultured AD fibroblasts, producing altered isoelectrophoretic forms of the enzyme transketolase (TK-alkaline bands). The TK profile and apolipoprotein E (APOE) genotype were examined in fibroblasts from 36 clinically diagnosed probable late-onset sporadic AD patients and 38 of their asymptomatic relatives, 29 elderly healthy individuals, 12 neurological non-AD patients, and 5 early-onset AD patients. TK alterations occurred in (i) several probable AD patients regardless of age-of-onset and severity of disease; (ii) all early-onset AD patients and APOEε4/4 carriers; and (iii) nearly half of asymptomatic AD relatives. Normal subjects and non-AD patients were all negative. Notably, culture conditions promoting TK alterations were also effective in increasing active BACE1 levels. Overall, the TK assay might represent a low-cost laboratory tool useful for supporting AD differential diagnosis and identifying asymptomatic subjects who are at greater risk of AD and who should enter a follow-up study. Moreover, the cultured fibroblasts were confirmed as a usefulin vitromodel for further studies on the pathogenetic process of AD.

scholarly journals A SERUM PROTEIN SIGNATURE OF APOE GENOTYPES IN CENTENARIANS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S621-S622
Author(s):  
Stefano Monti ◽  
Stefano Monti ◽  
Paola Sebastiani ◽  
Anastasia Gurinovich ◽  
Toshiko Tanaka ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Late Onset ◽  
Expression Profiles ◽  
Apoe Genotype ◽  
Cognitive Change ◽  
Serum Proteomics ◽  
Apoe Genotypes ◽  
Protein Signature

Abstract The discovery of treatments to prevent or delay Alzheimer’s disease is a priority. The gene APOE is associated with cognitive change and late onset Alzheimer’s disease, and epidemiological studies have shown that the e_2 allele of APOE has a neuroprotective effect, and it is associated with increased longevity. We correlated APOE genotype data of 222 New England Centenarian Study participants, including 79 centenarians, 84 centenarian offspring and 55 carriers of APOE e_2, with aptamer-based serum proteomics (SomaLogic technology) of 4783 human proteins corresponding to 4137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes, and replicated the signature in 3 independent studies. We show that the protein signature tracks with gene expression profiles in brains of late onset Alzheimer’s disease vs. healthy controls. Finally, we show that seven of these proteins correlate with cognitive function changes. Therefore, targeting APOE e_2 molecularly may preserve cognitive function.

scholarly journals Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 182 ◽  
Author(s):  
Brandon Farmer ◽  
Jude Kluemper ◽  
Lance Johnson
Keyword(s):  
Fatty Acid ◽  
Lipid Droplets ◽  
Consumption Rate ◽  
Acid Metabolism ◽  
Late Onset ◽  
Apoe Genotype ◽  
Lipid Droplet Formation ◽  
Perilipin 2 ◽  
E4 Allele ◽  
Carnitine Palmitoyltransferase 1

Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both E4 carriers and individuals with AD exhibit a state of cerebral lipid dyshomeostasis, we hypothesized that APOE may play a role in regulating LD metabolism. We found that astrocytes expressing E4 accumulate significantly more and smaller LDs compared to E3 astrocytes. Accordingly, expression of perilipin-2, an essential LD protein component, was higher in E4 astrocytes. We then probed fatty acid (FA) metabolism and found E4 astrocytes to exhibit decreased uptake of palmitate, and decreased oxidation of exogenously supplied oleate and palmitate. We then measured oxygen consumption rate, and found E4 astrocytes to consume more oxygen for endogenous FA oxidation and accumulate more LD-derived metabolites due to incomplete oxidation. Lastly, we found that E4 astrocytes are more sensitive to carnitine palmitoyltransferase-1 inhibition than E3 astrocytes. These findings offer the potential for further studies investigating the link between astrocyte lipid storage, utilization, and neurodegenerative disease as a function of APOE genotype.

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