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From the Department of Biochemistry,* Laboratory for Alzheimer’s and Parkinson’s Disease Research, Adolf Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany; the Center for Biochemistry, University of Cologne, Cologne, Germany; and the Department of Human Genetics, Experimental Genetics Group, K. U. Leuven, Leuven, Belgium
The generation of amyloid peptides (Aß) from the amyloid precursor protein (APP) is initiated by ß-secretase (BACE), whereas subsequent 
-secretase cleavage mediated by presenilin-1, produces Aß peptides mainly of 40 or 42 amino acids long. In addition, alternative ß'-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Aß(11-40/42) peptides, but the functional significance or pathological impact is unknown. Here we demonstrate that in the brain of BACE x APP[V717I] double-transgenic mice, amyloidogenic processing at both Asp1 and Glu11 is increased resulting in more and different Aß species and APP C-terminal fragments. Pathologically, BACE significantly increased the number of diffuse and senile amyloid plaques in old double-transgenic mice. Unexpectedly, vascular amyloid deposition was dramatically lower in the same BACE x APP[V717I] double-transgenic mice, relative to sex- and age-matched APP[V717I] single-transgenic mice in the same genetic background. The tight inverse relation of vascular amyloid to the levels of the less soluble N-terminally truncated Aß peptides is consistent with the hypothesis that vascular amyloid deposition depends on drainage of excess tissue Aß. This provides biochemical evidence in vivo for the preferential contribution of N-truncated Aß to parenchymal amyloid deposition in contrast to vascular amyloid pathology.
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