Novel aspects of accumulation dynamics and A beta composition in transgenic models of AD.
A homogeneous time-resolved fluorescence immunoassay for detection of beta-amyloid (A beta) peptides has been adapted for quantification of A beta(40) and A beta(42) accumulation in brains of APP695SWE transgenic mice. These over-express human beta APP(swe), beta-amyloid precursor protein (beta-APP) containing the K670N/M671L 'Swedish' familial Alzheimer's disease (FAD) mutation. Both peptides start to accumulate in this line from about 260 to 280 days of age. Co-expression of a human presenilin-1 (PS1) transgene containing the A246E FAD mutation accelerates deposition and also favors-at least initially-accumulation of A beta(42) so that the A beta(2):A beta(40) ratio of peptides from 7- to 12-month-old APP695SWE x PS1A246E animals is significantly elevated above that observed throughout the lifetime of APP695SWE mice. These findings, supported by parallel immunohistochemical staining and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry data, offer important longitudinal characterization of two mouse models of cerebral amyloidosis. Application of the same extraction and quantitation procedures to samples of temporal cortex from AD sufferers indicates however that A beta(40) is only a minor component of beta-amyloid in humans.
Department of Molecular and Cellular Neuroscience, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK.
Huw D
HD
Lewis
Dirk
D
Beher
David
D
Smith
Louise
L
Hewson
Natalie
N
Cookson
David S
DS
Reynolds
Gerard R
GR
Dawson
Michael
M
Jiang
Lex H T
LH
Van der Ploeg
Su
S
Qian
Thomas W
TW
Rosahl
Raj N
RN
Kalaria
Mark S
MS
Shearman
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D016231:Fluorescence Polarization Immunoassay / Q000379:methods; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D058225:Plaque, Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)