ABSTRACT
Findings from genetic, animal model, and human studies support the observation that accumulation of the ß-amyloid (Aß) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aß clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aß clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aß levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aß levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aß40 in the ISF are relatively stable and begin to decline within minutes of blocking Aß production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of Aß, resulted in significant prolongation of Aß40 half-life, but only in the latter phase of Aß clearance from the ISF.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Extracellular Fluid/metabolism , Hippocampus/metabolism , Peptide Fragments/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Animals , Disease Models, Animal , Electrodes , Humans , Mice , Mice, Mutant Strains , Peptide Fragments/geneticsABSTRACT
Precise spatiotemporal epigenetic regulation of the genome facilitates species-typical development; sexual differentiation of the brain by gonadal hormones and sex chromosomes causes extensive epigenetic reprogramming of many cells in the body, including the brain, and may indirectly predispose males and females to different psychiatric conditions. We and others have demonstrated sex differences in DNA methylation, as well as in the enzymes that form, or 'write', this epigenetic modification. However, while a growing body of evidence suggests that DNA methylation undergoes rapid turnover and is dynamically regulated in vivo, to our knowledge no studies have been done investigating whether sex differences exist in the epigenetic 'erasers' during postnatal development. Here we report sex differences in the expression of growth arrest and DNA damage inducible factor ß (Gadd45b), but not family members α (a) or γ (g), in the neonatal and juvenile rodent amygdala.
