ABSTRACT
Accumulation of beta-amyloid (Abeta) peptide in the brain is a major hallmark of Alzheimer's disease (AD). Hypercholesterolemia is a risk factor for AD and has been shown by laboratory studies to cause Abeta accumulation. Abeta levels in the brain are governed by its generation from amyloid precursor protein by beta-secretase (BACE1), degradation by the insulin degrading enzyme (IDE), clearance from the brain by the low density lipoprotein receptor-related protein (LRP-1), and transport from circulation into the brain by receptor for advanced glycation end products (RAGE). However, the mechanisms by which hypercholesterolemia causes Abeta accumulation in the brain and contributes to the pathogenesis of AD are still to be determined. In the present study, we determined the extent to which hypercholesterolemia-induced Abeta accumulation is associated with alterations in BACE1, IDE, LRP-1, and RAGE expression levels. We show that hypercholesterolemia increases Abeta production, an effect that is associated with increased levels of BACE1 and RAGE and reduced levels of IDE and LRP-1. These results suggest that reducing Abeta accumulation in the brain may require strategies that combine reduction of generation and transport of Abeta in addition to acceleration of degradation and clearance of this peptide.
Subject(s)
Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Brain/metabolism , Hypercholesterolemia/metabolism , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/enzymology , Cholesterol, Dietary , Disease Models, Animal , Hypercholesterolemia/complications , Hypercholesterolemia/etiology , Insulysin/metabolism , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Male , Rabbits , Receptor for Advanced Glycation End Products , Receptors, Immunologic/metabolismABSTRACT
Since alterations in monoamines and monoamine oxidase (MAO) have been postulated to play a role in toxic effects of lead (Pb) on the central nervous system, we have examined the protective effects of calcium (Ca2+) and zinc (Zn2+) supplementation on Pb-induced perturbations in the levels of monoamines and the activity of MAO. Swiss albino mice were lactationally exposed to low (0.2%) and high (1%) levels of Pb-acetate via drinking water of the mother. Pb-exposure commenced on postnatal day (PND) 1, continued up to PND 21 and stopped at weaning. Ca2+ or Zn2+ (0.02% in 0.2% Pb-water or 0.1% in 1% Pb-water) was supplemented separately to the mother up to PND 21. The levels of monoamines (epinephrine, norepinephrine, dopamine and serotonin) and the activity of MAO in the brain regions such as hippocampus, cortex, cerebellum and medulla of young (1 month old) and adult (3 month old) mice were determined in the synaptosomal fractions. The synaptosomal monoamines though increased with low level (0.2%) Pb-exposure, significantly decreased with high level (1%) Pb-exposure in all the brain regions in both the age groups. In general, the young mice seem to be more vulnerable to Pb-neurotoxicity. Ca2+ or Zn2+ supplementation significantly reversed the Pb-induced perturbations both in the levels of monoamines and in the activity of MAO. However, the recovery in monoamine levels and MAO activity was more pronounced with Ca2+ supplementation as compared to Zn2+. These results provide evidence that dietary Ca2+ and/or Zn2+ provide protection against Pb-induced neurotoxic effects.
Subject(s)
Brain/drug effects , Brain/growth & development , Calcium/administration & dosage , Lead Poisoning, Nervous System/prevention & control , Lead/toxicity , Zinc/administration & dosage , Animals , Animals, Suckling , Biogenic Monoamines/chemistry , Biogenic Monoamines/metabolism , Brain/metabolism , Brain Chemistry/drug effects , Drug Administration Routes , Female , Lead Poisoning, Nervous System/drug therapy , Lead Poisoning, Nervous System/metabolism , Male , Maternal Exposure , Mice , Monoamine Oxidase/metabolism , Reproducibility of Results , Sensitivity and Specificity , Spectrophotometry, Ultraviolet/methods , Synaptosomes/drug effects , Synaptosomes/enzymologyABSTRACT
Botanical insecticides are relatively safe and biodegradable, and are readily available sources of bioinsecticides. In recent years, the neem derivative, azadirachtin, has been examined as an alternative to synthetic insecticides because of its broad-spectrum insecticidal action. Because many of the natural products and synthetic compounds used in the control of insect pests are known to exhibit electrophysiological effects, in this paper we focused our studies on the alterations in the activity of the enzyme acetylcholinesterase (AChE) and electrical activity in the nervous system of the cockroach, Periplaneta americana, exposed to azadirachtin. Exposure to azadirachtin produced an excitatory effect on spontaneous electrical activity as well as cercal sensory-mediated giant-fiber responses in the cockroach. Topical exposure to sublethal doses of azadirachtin did not result in any significant alterations in the AChE activity in different regions of the nervous system. We suggest that azadirachtin exerts excitatory action on the electrical activity in the nervous system of cockroach by interfering with the ion channels in the nerve membrane, the probable target of several insecticides.
