ABSTRACT
We previously developed single App knock-in mouse models of Alzheimer's disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and evaluated its characteristics. Amyloid ß peptide (Aß) pathology was exhibited by AppG-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aß-secretase inhibitor, verubecestat, attenuated Aß production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of ß-secretase inhibition given that most patients with AD do not carry the Swedish mutations. Comparison of isogenic App knock-in lines revealed that multiple factors, including elevated C-terminal fragment ß (CTF-ß) and humanization of Aß might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic App, knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Peptides/genetics , Animals , Gene Knock-In Techniques , Humans , Mice , Mice, TransgenicABSTRACT
We measured changes in histamine and tryptase levels in fluid of children with atopic dermatitis using skin chamber methods and evaluated the correlation with clinical symptoms. Skin chambers were applied to forearm skin which had been scratched with a needle, and an extract of Dermatophagoides farinae (mite antigen) at 50 µg/ml in saline was added through 0.3-µm filters as a challenge. We measured the concentrations of tryptase and histamine 2, 6, 12, and 24 h after challenge. The skin chamber test was done before and after hospitalization therapy or beach camp therapy. We also tested patients with atopic dermatitis of varying severity, asthmatic patients without dermatitis, and normal volunteers. The histamine levels dramatically increased 24 h after challenge with mite antigen in patients with severe atopic dermatitis, whereas this was not observed in patients with mild atopic dermatitis or asthma and in normal volunteers. The levels of histamine in the chambers 24 h after challenge decreased along with improvement of skin condition after various kinds of treatment and beach camp therapy. These results indicate that the skin chamber test will be a useful objective tool to evaluate the skin conditions of patients with atopic dermatitis. The increase of histamine level was not accompanied by an increase in tryptase level, suggesting the importance of basophil activation in this disease.
