amyloid-beta-peptides and Hyperglycemia

Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aβ), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aβ, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD.. Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aβ, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aβ were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aβ for both hyperglycemia and AD. Additionally, HNE-Aβ peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD.. Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes.

Topics: Aged; Aged, 80 and over; Aldehydes; Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Antibodies, Neutralizing; Autoantibodies; Biomarkers; Blood Proteins; Case-Control Studies; Female; Humans; Hyperglycemia; Male; Peptide Fragments

We hypothesized that hyperglycemia-induced mitochondrial dysfunction and oxidative stress are closely associated with amyloid-β peptide (Aβ) toxicity in endothelial cells. Brain microvascular endothelial cells from rat (RBMEC) and mice (MBMEC) were isolated from adult Sprague-Dawley rats and homozygous db/db (Leprdb/Leprdb) and heterozygous (Dock7m/Leprdb) mice, and cultured under normo- and hyperglycemic conditions for 7 d followed by 24 h exposure to Aβ1-40. Some experiments were also performed with two mitochondrial superoxide (O2•-) scavengers, MitoTempo and Peg-SOD. Cell viability was measured by the Alamar blue assay and mitochondrial membrane potential (ΔΨm) by confocal microscopy. Mitochondrial O2•- and hydrogen peroxide (H2O2) production was assessed by fluorescence microscopy and H2O2 production was confirmed by microplate reader. Hyperglycemia or Aβ1-40 alone did not affect cell viability in RBMEC. However, the simultaneous presence of high glucose and Aβ1-40 reduced cell viability and ΔΨm, and enhanced mitochondrial O2•- and H2O2 production. MitoTempo and PEG-SOD prevented Aβ1-40 toxicity. Interestingly, MBMEC presented a similar pattern of alterations with db/db cultures presenting higher susceptibility to Aβ1-40. Overall, our results show that high glucose levels increase the susceptibility of brain microvascular endothelial cells to Aβ toxicity supporting the idea that hyperglycemia is a major risk factor for vascular injury associated with AD.

Topics: Amyloid beta-Peptides; Animals; Brain; Cells, Cultured; Disease Susceptibility; Endothelial Cells; Glucose; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Hydrogen Peroxide; Hyperglycemia; Male; Membrane Potential, Mitochondrial; Mice; Mice, Mutant Strains; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Leptin; Time Factors

Age-related neurodegenerative dementia, particularly Alzheimer's disease (AD), may be exacerbated by several interacting risk factors including genetic predisposition, beta amyloid (A beta) protein accumulation, environmental toxins, head trauma, and abnormal glycolytic metabolism. We examined the spatial learning and memory effects of A beta(1-40) administration on hyperglycemic mice by their performance in the Morris water maze. Chronic hyperglycemia was induced in male C57BL/6J mice to mimic diabetes mellitus by intraperitoneal injection of streptozotocin (STZ), which specifically destroys pancreatic beta-islet cells. Ten days after STZ treatment, intrahippocampal infusion of vehicle, monomer, or oligomer A beta(1-40) was given to these hyperglycemic mice. Our results demonstrate that in comparison with vehicle or monomer A beta(1-40), oligomer A beta(1-40) induced significant deficits of spatial learning and memory in hyperglycemic mice. Apoptotic signals were identified in the CA1 and dentate gyrus of hippocampus in hyperglycemic mice. A beta accumulation, oxidative stress, and apoptosis in the CA1 region were more intensive in hyperglycemic mice than that in normoglycemic mice after acute treatment with oligomer A beta(1-40) peptide treatment. These results indicate that CA1 apoptosis was enhanced by oxidative stress resulting from accumulation of A beta. Considered together, these findings suggest that hyperglycemic mice are more vulnerable to the A beta-induced-oxidative stress than normal subjects. We therefore propose that A beta accumulation would be enhanced by hyperglycemia, and the oxidative stress caused by A beta accumulation would in turn enhance the AD symptoms.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; Blood Glucose; Diabetes Mellitus, Experimental; Discrimination Learning; Hippocampus; Hyperglycemia; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microinjections; Neurons; Peptide Fragments; Spatial Behavior