0000000000083692
AUTHOR
Anja Schroeder
A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model
Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 i…
Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases
Cleavage of the amyloid precursor protein (APP) within the amyloid-beta (Aβ) sequence by the α-secretase prevents the formation of toxic Aβ peptides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17) act as α-secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsα. Here we demonstrate that the related APP-like protein 2 (APLP2), which has been shown to be essential for development and survival of mice, is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma c…
Gradient-echo and CRAZED imaging for minute detection of Alzheimer plaques in an APPV717I x ADAM10-dn mouse model.
Different strategies to visualize amyloid plaques with MRI at 17.6 Tesla were investigated in a novel mouse model of Alzheimer's disease (AD). Large iron-containing plaques were observed in the thalamus, but cortical plaques did not show iron deposits. Plaques in the thalamus were visualized in vivo with the use of low-resolution, 3D gradient-echo (GRE) imaging in 82 s, and with 94-microm resolution in 34 min. The feasibility of obtaining bright contrast from plaques using the COSY revamped with asymmetric z-GRE detection (CRAZED) technique was investigated in experiments on fixed brains. The original CRAZED approach provided reduced signal near the plaques (similarly to GRE imaging) and ad…
Effect of a dominant-negative form of ADAM10 in a mouse model of Alzheimer's disease.
The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid-beta protein precursor (AbetaPP) within the region of the amyloid-beta peptides to prevent their formation and aggregation in the brain. Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AbetaPP (ADAM10 x APP[V717I]) alleviated functional deficits related to Alzheimer's disease. To further demonstrate that this is due to the specific activity of alpha-secretase, we characterized mice overexpressing an inactive form of ADAM10 (ADAM10[E384A]; ADAM10-dn). T…
Over-expression of two different forms of the α-secretase ADAM10 affects learning and memory in mice
Members of the ADAM family (adisintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid precursor protein within the region of the Abeta peptides preventing their aggregation in the brain. The increase of alpha-secretase activity in the brain provides a plausible strategy to prevent Abeta formation. Concerning this possibility two transgenic mouse lines (FVB/N) have been created: mice over-expressing the bovine form of the alpha-secretase (ADAM10) and mice over-expressing an inactive form of the alpha-secretase (ADAM10-E348A-HA; ADAM10-dn). For behavioral examination a F1 ge…