Abeta42 is essential for parenchymal and vascular amyloid deposition in mice.
Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.
McGowan
Eileen
E
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Pickford
Fiona
F
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Kim
Jungsu
J
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Onstead
Luisa
L
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Eriksen
Jason
J
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Yu
Cindy
C
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Skipper
Lisa
L
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Murphy
M Paul
MP
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Beard
Jenny
J
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Das
Pritam
P
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Jansen
Karen
K
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
DeLucia
Michael
M
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Lin
Wen-Lang
WL
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Dolios
Georgia
G
Department of Human Genetics Mount Sinai School of Medicine New York, New York 10029.
Wang
Rong
R
Department of Human Genetics Mount Sinai School of Medicine New York, New York 10029.
Eckman
Christopher B
CB
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Dickson
Dennis W
DW
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Hutton
Mike
M
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Hardy
John
J
Laboratory of Neurogenetics National Institute on Aging National Institutes of Health Bethesda, Maryland 20892.
Golde
Todd
T
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010841:Pia Mater / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T