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). Three lines of mice (controls (C57Bl/6 x FVB), APP[V717I[ transgenics and ADAM10-dn x APP[V717I] double-transgenics) were investigated with respect to learning and memory in the Morris water maze. Double-transgenic mice overexpressing ADAM10-dn behaved similar to APP[V717I] overexpressing mice. This provides further evidence that ADAM10 in vivo by its enzymatic activity is able to counteract cognitive deficits. Stimulation of alpha-secretase activity might thus be a suitable approach to study treatment strategies of Alzheimer's disease.
Schroeder
Anja
A
Central Laboratory Animal Facility (ZVTE), Johannes Gutenberg University Mainz, Mainz, Germany. anschroe@uni-mainz.de
Fahrenholz
Falk
F
Schmitt
Ulrich
U
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011930:Reaction Time / Q000235:genetics; D013550:Swimming; D014633:Valine / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D007532:Isoleucine; D018698:Glutamic Acid; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D014633:Valine; D000409:Alanine