Rodent A beta modulates the solubility and distribution of amyloid deposits in transgenic mice.
The amino acid sequence of amyloid precursor protein (APP) is highly conserved, and age-related A beta aggregates have been described in a variety of vertebrate animals, with the notable exception of mice and rats. Three amino acid substitutions distinguish mouse and human A beta that might contribute to their differing properties in vivo. To examine the amyloidogenic potential of mouse A beta, we studied several lines of transgenic mice overexpressing wild-type mouse amyloid precursor protein (moAPP) either alone or in conjunction with mutant PS1 (PS1dE9). Neither overexpression of moAPP alone nor co-expression with PS1dE9 caused mice to develop Alzheimer-type amyloid pathology by 24 months of age. We further tested whether mouse A beta could accelerate the deposition of human A beta by crossing the moAPP transgenic mice to a bigenic line expressing human APPswe with PS1dE9. The triple transgenic animals (moAPP x APPswe/PS1dE9) produced 20% more A beta but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings. Instead, the additional mouse A beta increased the detergent solubility of accumulated amyloid and exacerbated amyloid deposition in the vasculature. These findings suggest that, although mouse A beta does not influence the rate of amyloid formation, the incorporation of A beta peptides with differing sequences alters the solubility and localization of the resulting aggregates.
Jankowsky
Joanna L
JL
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Younkin
Linda H
LH
Gonzales
Victoria
V
Fadale
Daniel J
DJ
Slunt
Hilda H
HH
Lester
Henry A
HA
Younkin
Steven G
SG
Borchelt
David R
DR
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D053764:Presenilin-1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012995:Solubility; D019076:Transgenes
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010455:Peptides; D053764:Presenilin-1