Regular Articles
β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE × APP[V717I] Double-Transgenic Mice

https://doi.org/10.1016/S0002-9440(10)63419-0Get rights and content

The generation of amyloid peptides (Aβ) from the amyloid precursor protein (APP) is initiated by β-secretase (BACE), whereas subsequent γ-secretase cleavage mediated by presenilin-1, produces Aβ peptides mainly of 40 or 42 amino acids long. In addition, alternative β′-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Aβ(11-40/42) peptides, but the functional significance or pathological impact is unknown. Here we demonstrate that in the brain of BACE × APP[V717I] double-transgenic mice, amyloidogenic processing at both Asp1 and Glu11 is increased resulting in more and different Aβ 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 × 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 Aβ peptides is consistent with the hypothesis that vascular amyloid deposition depends on drainage of excess tissue Aβ. This provides biochemical evidence in vivo for the preferential contribution of N-truncated Aβ to parenchymal amyloid deposition in contrast to vascular amyloid pathology.

Cited by (0)

Supported by the European Economic Community-Fifth Framework Program, the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, the Rooms Fund, the K.U. Leuven Special Research Fund, K.U. Leuven Research and Development, the Deutsche Forschungsgemeinschaft (SFB 596), and Boehringer-Ingelheim (to C.H.).

M.W. and I.D. contributed equally to this work.

View Abstract