ABSTRACT
Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-ß protein precursor (AßPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aß pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aß deposits in the 10-month-old transgenic mutant human AßPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AßPPα, but low levels of amyloidogenic ß-secretase and γ-secretase, and a neurotoxic product, Aß42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed ß-secretase and γ-secretase, but not α-secretase, which could increase Aß generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48âh following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AßPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AßPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Gene Expression Regulation/physiology , Hippocampus/cytology , Neurons/metabolism , Peptide Fragments/metabolism , ADAM10 Protein/immunology , ADAM10 Protein/metabolism , Amyloid Precursor Protein Secretases/genetics , Animals , Antibodies/pharmacology , Aspartic Acid Endopeptidases/metabolism , Cell Count , Dose-Response Relationship, Drug , Female , Hippocampus/drug effects , Humans , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Male , Mice , Mice, Transgenic , Middle Aged , Mutation/genetics , Presenilin-1/genetics , Species Specificity , Time FactorsABSTRACT
The phenyl ring in the title compound, C(15)H(14)ClF(4)NO, makes a dihedral angle of 80.3â (3)° with the cyclo-propane ring. In the crystal, mol-ecules are linked by N-Hâ¯O hydrogen bonds into chains running along the a axis.
ABSTRACT
In the title compound, C(15)H(14)Cl(2)F(3)NO, synthesized by the reaction of 3-[(E)-2-chloro-3,3,3-trifluoro-prop-1-en-yl]-2,2-dimethyl-cyclo-propane-carb-oxy-lic acid and 2-chloro-aniline, the aromatic ring makes a dihedral angle of 76.7â (3)° with the plane of the cyclo-propane ring. In the crystal, inter-molecular N-Hâ¯O hydrogen bonds link the mol-ecules into chains running along the b axis.
ABSTRACT
AIM: To express capsid tail protein P11 of T7 bacteriophage and produce mouse monoclonal antibody(mAb) against the protein. METHODS: P11 protein was cloned and recombinant P11 protein was expressed as a fusion protein with an N-terminal 6-His tag. The purified protein was used to immunize BALB/c mouse. The specificity of mAb was analyzed by ELISA and Western blot. RESULTS: P11 protein was successfully expressed and purified. SDS-PAGE analysis showed that the molecular weight of the expressed protein was approximately 27 kd. One hybridoma cell (2G11) secreting mAb against P11 was developed. The isotype of the mAb was IgG(2b). ELISA detection showed that titers of mAb was 1:8. 1 x 10(5) in ascites.Western blot analysis proved mAb obtained could react specifically to the recombinant p11 protein. CONCLUSION: Recombinant P11 protein and mAbs were successfully prepared.
