Abeta40 inhibits amyloid deposition in vivo.
Numerous studies have established a pivotal role for Abeta42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Abeta40 is the predominant form of amyloid beta (Abeta) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in Abeta40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Abeta40 mice that selectively express high levels of Abeta40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Abeta42A mice expressing Abeta42 selectively and analyzed parenchymal and cerebrovascular Abeta deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Abeta40 decreased Abeta deposition by 60-90%. These results demonstrate that Abeta42 and Abeta40 have opposing effects on amyloid deposition: Abeta42 promotes amyloid deposition but Abeta40 inhibits it. In addition, increasing Abeta40 levels protected BRI-Abeta40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Abeta40 with respect to amyloid deposition suggest that strategies that preferentially target Abeta40 may actually worsen the disease course and that selective increases in Abeta40 levels may actually reduce the risk for development of AD.
Kim
Jungsu
J
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
Onstead
Luisa
L
Randle
Suzanne
S
Price
Robert
R
Smithson
Lisa
L
Zwizinski
Craig
C
Dickson
Dennis W
DW
Golde
Todd
T
McGowan
Eileen
E
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)