Dataset Information

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer's Dementia.

ABSTRACT: Nowadays, Alzheimer's disease (AD) is a severe sociological and clinical problem. Since it was first described, there has been a constant increase in its incidence and, for now, there are no effective treatments since current approved medications have only shown short-term symptomatic benefits. Therefore, it is imperative to increase efforts in the search for molecules and non-pharmacological strategies that are capable of slowing or stopping the progress of the disease and, ideally, to reverse it. The amyloid cascade hypothesis based on the fundamental role of amyloid has been the central hypothesis in the last 30 years. However, since amyloid-directed treatments have shown no relevant beneficial results other theories have been postulated to explain the origin of the pathology. The brain is a highly metabolically active energy-consuming tissue in the human body. It has an almost complete dependence on the metabolism of glucose and uses most of its energy for synaptic transmission. Thus, alterations on the utilization or availability of glucose may be cause for the appearance of neurodegenerative pathologies like AD. In this review article, the hypothesis known as Type 3 Diabetes (T3D) will be evaluated by summarizing some of the data that has been reported in recent years. According to published research, the adherence over time to low saturated fatty acids diets in the context of the Mediterranean diet would reduce the inflammatory levels in brain, with a decrease in the pro-inflammatory glial activation and mitochondrial oxidative stress. In this situation, the insulin receptor pathway would be able to fine tune the mitochondrial biogenesis in neuronal cells, regulation the adenosine triphosphate/adenosine diphosphate intracellular balance, and becoming a key factor involved in the preservation of the synaptic connexions and neuronal plasticity. In addition, new targets and strategies for the treatment of AD will be considered in this review for their potential as new pharmacological or non-pharmacological approaches.

SUBMITTER: Folch J

PROVIDER: S-EPMC6743006 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer's Dementia.

Folch Jaume J Olloquequi Jordi J Ettcheto Miren M Busquets Oriol O Sánchez-López Elena E Cano Amanda A Espinosa-Jiménez Triana T García Maria Luisa ML Beas-Zarate Carlos C Casadesús Gemma G Bulló Mónica M Auladell Carme C Camins Antoni A

Frontiers in aging neuroscience 20190906

Nowadays, Alzheimer's disease (AD) is a severe sociological and clinical problem. Since it was first described, there has been a constant increase in its incidence and, for now, there are no effective treatments since current approved medications have only shown short-term symptomatic benefits. Therefore, it is imperative to increase efforts in the search for molecules and non-pharmacological strategies that are capable of slowing or stopping the progress of the disease and, ideally, to reverse ...[more]

PMID: 31551756

Similar Datasets

Project description:Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.

Project description:Obesity causes inflammation and insulin resistance in the vasculature as well as in tissues involved in glucose metabolism such as liver, muscle, and adipose tissue. To investigate the relative susceptibility of vascular tissue to these effects, we determined the time course over which inflammation and insulin resistance develops in various tissues of mice with diet-induced obesity (DIO) and compared these tissue-based responses to changes in circulating inflammatory markers.Adult male C57BL/6 mice were fed either a control low-fat diet (LF; 10% saturated fat) or a high-fat diet (HF, 60% saturated fat) for durations ranging between 1 to 14 weeks. Cellular inflammation and insulin resistance were assessed by measuring phospho-IkappaBalpha and insulin-induced phosphorylation of Akt, respectively, in extracts of thoracic aorta, liver, skeletal muscle, and visceral fat. As expected, HF feeding induced rapid increases of body weight, fat mass, and fasting insulin levels compared to controls, each of which achieved statistical significance within 4 weeks. Whereas plasma markers of inflammation became elevated relatively late in the course of DIO (eg, serum amyloid A [SAA], by Week 14), levels of phospho-IkappaBalpha in aortic lysates were elevated by 2-fold within the first week. The early onset of vascular inflammation was accompanied by biochemical evidence of both endothelial dysfunction (reduced nitric oxide production; induction of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) and insulin resistance (impaired insulin-induced phosphorylation of Akt and eNOS). Although inflammation and insulin resistance were also detected in skeletal muscle and liver of HF-fed animals, these responses were observed much later (between 4 and 8 weeks of HF feeding), and they were not detected in visceral adipose tissue until 14 weeks.During obesity induced by HF feeding, inflammation and insulin resistance develop in the vasculature well before these responses are detected in muscle, liver, or adipose tissue. This observation suggests that the vasculature is more susceptible than other tissues to the deleterious effects of nutrient overload.

Project description:BackgroundDegradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD.ObjectiveTo quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI).Methods60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%).ResultsAll FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups.ConclusionsAll three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.

Dataset Information

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer's Dementia.

Publications

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer's Dementia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets