amyloid-beta-peptides and Diabetes-Mellitus--Type-2

Plasma amyloid-β (Aβ) levels have rarely been investigated in type 2 diabetes despite its known associations with Alzheimer's disease.. To compare blood plasma Aβ concentrations (Aβ40 and Aβ42) in cognitively normal individuals with and without type 2 diabetes.. Plasma Aβ40 and Aβ42 were measured in 194 participants with diabetes recruited from the community-based Fremantle Diabetes Study Phase II cohort (mean age 71 years, 59% males) and 194 age-, sex-, and APOEɛ4 allele-matched, control subjects without diabetes from the Australian Imaging, Biomarkers and Lifestyle Study using a multiplex microsphere-based immunoassay.. Plasma Aβ40 and Aβ42 were normally distributed in the controls but were bimodal in the participants with diabetes. Median Aβ40 and Aβ42 concentrations were significantly lower in those with type 2 diabetes (Aβ40 median [inter-quartile range]: 125.0 [52.6-148.3] versus 149.3 [134.0-165.6] pg/mL; Aβ42: 26.9 [14.5-38.3] versus 33.6 [28.0-38.9] pg/mL, both p < 0.001) while the ratio Aβ42:Aβ40 was significantly higher (0.26 [0.23-0.32] versus 0.22 [0.19-0.25], p < 0.001). After adjustment, participants with diabetes and plasma Aβ40 levels in the low peak of the bimodal distribution were significantly more likely to have normal to high estimated glomerular filtration rates (odds ratio (95% CI): 2.40 (1.20-4.80), p = 0.013) although the group with diabetes had lower renal function overall.. Type 2 diabetes is associated with altered plasma concentrations of Aβ peptides and is an important source of variation that needs to be taken into account when considering plasma Aβ peptides as biomarkers for Alzheimer's disease.

Topics: Aged; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Longitudinal Studies; Male; Peptide Fragments

To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid β (Aβ) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice.. Aβ influx across the BBB was determined by intra-arterial infusion of. Downregulation of abnormal Aβ influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice.

Topics: Amyloid beta-Peptides; Animals; bcl-2-Associated X Protein; Benzamides; Blood-Brain Barrier; Brain; Caspase 3; Cognition Disorders; Diabetes Mellitus, Type 2; Disease Models, Animal; Exploratory Behavior; Male; Maze Learning; Mice; Microvessels; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Receptor for Advanced Glycation End Products; Receptors, Leptin; Synaptic Transmission

Increased coexistence of Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) suggests that insulin resistance abets neurodegenerative processes, but linkage mechanisms are obscure. Here, we examined insulin signaling factors in brains of insulin-resistant high-fat-fed mice, ob/ob mice, mice with genetically impaired muscle glucose transport, and monkeys with diet-dependent long-standing obesity/T2DM. In each model, the resting/basal activities of insulin-regulated brain protein kinases, Akt and atypical protein kinase C (aPKC), were maximally increased. Moreover, Akt hyperactivation was accompanied by hyperphosphorylation of substrates glycogen synthase kinase-3β and mammalian target of rapamycin and FOXO proteins FOXO1, FOXO3A, and FOXO4 and decreased peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression. Akt hyperactivation was confirmed in individual neurons of anterocortical and hippocampal regions that house cognition/memory centers. Remarkably, β-amyloid (Aβ1-40/42) peptide levels were as follows: increased in the short term by insulin in normal mice, increased basally in insulin-resistant mice and monkeys, and accompanied by diminished amyloid precursor protein in monkeys. Phosphorylated tau levels were increased in ob/ob mice and T2DM monkeys. Importantly, with correction of hyperinsulinemia by inhibition of hepatic aPKC and improvement in systemic insulin resistance, brain insulin signaling normalized. As FOXOs and PGC-1α are essential for memory and long-term neuronal function and regeneration and as Aβ1-40/42 and phospho-tau may increase interneuronal plaques and intraneuronal tangles, presently observed aberrations in hyperinsulinemic states may participate in linking insulin resistance to AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cell Cycle Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Forkhead Box Protein O1; Forkhead Box Protein O3; Forkhead Transcription Factors; Insulin; Insulin Resistance; Macaca mulatta; Male; Mice; Neurons; Obesity; Peptide Fragments; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Protein Kinase C; Proto-Oncogene Proteins c-akt; Signal Transduction; tau Proteins

The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the "regulatory landscape" of APP.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Cell Survival; Diabetes Mellitus, Type 2; Genetic Techniques; Genome-Wide Association Study; Humans; Metabolic Networks and Pathways; Peptide Fragments; Protein Processing, Post-Translational; Proteolysis; RNA, Small Interfering; Serum Amyloid A Protein

Increasing amounts of evidence suggest that Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to each other. We have recently identified in vitro a high affinity interaction between β-amyloid peptide (Aβ) of AD and islet amyloid polypeptide (IAPP) of T2D which results in the formation of non-fibrillar and non-cytotoxic Aβ-IAPP hetero-oligomers. The Aβ-IAPP interaction delays cytotoxic self-association of both polypeptides albeit it is unable to block it. In this context, IAPP-GI, a soluble conformationally constrained mimic of a non-amyloidogenic and non-toxic IAPP conformer, completely blocks Aβ amyloidogenesis and cytotoxicity. Here we studied the hetero-association pathways of Aβ with IAPP and with IAPP-GI. We found that preformed Aβ or IAPP fibrils and cytotoxic assemblies are able to seed amyloidogenesis and cytotoxicity in Aβ-IAPP but not in Aβ-IAPP-GI solutions. Initially non-fibrillar and non-toxic Aβ-IAPP but not Aβ-IAPP-GI hetero-oligomers were found to further aggregate into hetero-fibrils and cytotoxic assemblies in a process strongly enhanced under Aβ or IAPP self-assembly promoting conditions. Importantly, our studies provided evidence that initially non-fibrillar and non-toxic Aβ-IAPP hetero-oligomers are able to misfold into hetero-fibrils and indicated a crucial role of the strong amyloidogenic character of IAPP in this process. These results uncover a novel molecular property of the Aβ and IAPP sequences, i.e. their ability to form hetero-fibrils, and offer mechanistic support to a model linking Aβ and IAPP hetero-association to their cytotoxic self-association pathways and thus likely to the pathogenesis of AD and T2D.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid; Amyloid beta-Peptides; Amyloidosis; Animals; Benzothiazoles; Cell Survival; Circular Dichroism; Diabetes Mellitus, Type 2; Islet Amyloid Polypeptide; Kinetics; Microscopy, Electron, Transmission; Molecular Sequence Data; PC12 Cells; Peptide Fragments; Protein Binding; Protein Folding; Protein Multimerization; Rats; Spectrometry, Fluorescence; Thiazoles

To explore the relationship of the impairment of human umbilical vein endothelial cell (HUVEC) with amyloid-β.. HUVECs were cultured in the serum of patients with type 2 diabetes mellitus (DM) or serum of healthy control (HC), while fetal bovine serum (FBS) was used as a negative control. The proliferative activity of HUVEC were assessed by thiazolyl blue tetrazolium bromide (MTT) after 72 h. The supernatant concentrations of superoxide dismutase (SOD), maleic dialdehyde (MDA), nitric oxide (NO), amyloid-β40 (Aβ40) and Aβ42 were measured after 0.5, 3 and 72 h respectively.. Glycosylated hemoglobin values, fasting plasma glucose and fasting plasma Aβ40 concentrations of diabetic patients were higher than those of healthy counterparts (P < 0.01). Proliferative activity of HUVECs in group DM were significantly lower than that of group HC. Both group and the time of intervention had crossover effects on the levels of MDA, SOD, NO and Aβ40 ((163 ± 64), (207 ± 69), (286 ± 75) ng/L in group DM; (146 ± 76), (154 ± 75), (161 ± 72) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05) and Aβ42 ((48 ± 46), (54 ± 43), (79 ± 44) ng/L in group DM; (41 ± 12), (44 ± 16), (48 ± 12) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05). With the elongating time of intervention, the levels of SOD and NO decreased significantly in group DM and reached the lowest after 72 h while increased significantly in groups HC and FBS and peaked after 72 h. The concentrations of MDA, Aβ40 and Aβ42 increased significantly in all three groups while the fastest and marked increments were found in group DM (P < 0.01). Pearson correlation analysis showed that SOD was negatively correlated with Aβ40 (r = -0.482, P = 0.02) and Aβ42 (r = -0.422, P = 0.02) while MDA positively with Aβ40 (r = 0.418, P < 0.05) and Aβ42 (r = 0.833, P < 0.05) after 72 h.. Oxidative stress of vascular endothelial cells may be correlated with Aβ40 and Aβ42 in diabetes.

Topics: Aged; Amyloid beta-Peptides; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; Malondialdehyde; Middle Aged; Nitric Oxide; Oxidative Stress; Peptide Fragments; Superoxide Dismutase

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid; Amyloid beta-Peptides; Binding Sites; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Molecular Sequence Data; Peptide Fragments; Protein Binding

The hepatic clearance of amyloid beta-peptide (1-40) [Abeta(1-40)] from plasma, which is largely mediated by low-density lipoprotein receptor-related protein (LRP-1), is suggested to play a role in preventing Abeta(1-40) accumulation in the brain. Epidemiological investigations suggest a high incidence of cerebral Abeta deposition in insulin-resistant type II diabetes mellitus. The purpose of this study was to clarify the effect of insulin on the hepatic clearance of Abeta(1-40). LRP-1 expression on the hepatic plasma membrane was increased in a time-dependent manner by portal infusion of insulin and was 2.2-fold greater than that in nontreated controls after a 10-min infusion, whereas the expression in whole lysate was not affected by insulin treatment. The apparent hepatic uptake of [(125)I]Abeta(1-40) was also induced by insulin in a time-dependent manner. The increase in [(125)I]Abeta(1-40) uptake by insulin was concentration-dependent (EC(50) = 230 pM) and was completely abolished by receptor-associated protein (2 muM), an LRP-1 inhibitor. In conclusion, plasma insulin facilitates LRP-1 translocation to the hepatic plasma membrane from the intracellular pool, resulting in significant enhancement of hepatic Abeta(1-40) uptake from the circulating blood. The presently proposed mechanism would explain the epidemiological results demonstrating that type II diabetes mellitus is a risk factor of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Membrane; Diabetes Mellitus, Type 2; Hepatocytes; Insulin; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Peptide Fragments; Protein Transport; Rats; Rats, Sprague-Dawley

Using brain mitochondria isolated from 20-month-old diabetic Goto-Kakizaki rats, we evaluated the efficacy of CoQ10 treatment against mitochondrial dysfunction induced by Abeta1-40. For that purpose, several mitochondrial parameters were evaluated: respiratory indexes (RCR and ADP/O ratio), transmembrane potential (DeltaPsim), repolarization lag phase, repolarization and ATP levels and the capacity of mitochondria to produce hydrogen peroxide. We observed that 4 microM Abeta1-40 induced a significant decrease in the RCR and ATP content and a significant increase in hydrogen peroxide production. CoQ10 treatment attenuated the decrease in oxidative phosphorylation efficiency and avoided the increase in hydrogen peroxide production induced by the neurotoxic peptide. These results indicate that CoQ10 treatment counteracts brain mitochondrial alterations induced by Abeta1-40 suggesting that CoQ10 therapy can help to avoid a drastic energy deficiency that characterizes diabetes and Alzheimer's disease pathophysiology.

Topics: Adenosine Triphosphate; Age Factors; Amyloid beta-Peptides; Animals; Antioxidants; Brain; Cell Respiration; Coenzymes; Diabetes Mellitus, Type 2; Hydrogen Peroxide; Male; Membrane Potentials; Mitochondria; Oxidative Phosphorylation; Peptide Fragments; Rats; Rats, Wistar; Ubiquinone