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The Journal of Neuroscience, January 17, 2007, 27(3):627-633; doi:10.1523/JNEUROSCI.4849-06.2007
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Neurobiology of Disease
Aß40 Inhibits Amyloid Deposition In Vivo
Jungsu Kim, Luisa Onstead, Suzanne Randle, Robert Price, Lisa Smithson, Craig Zwizinski, Dennis W. Dickson, Todd Golde, andEileen McGowan Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224
Correspondence should be addressed to Dr. Eileen McGowan, Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224. Email: mcgowan.eileen{at}mayo.edu
Numerous studies have established a pivotal role for Aß42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Aß40 is the predominant form of amyloid ß (Aß) 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 Aß40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Aß40 mice that selectively express high levels of Aß40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Aß42A mice expressing Aß42 selectively and analyzed parenchymal and cerebrovascular Aß deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Aß40 decreased Aß deposition by 60–90%. These results demonstrate that Aß42 and Aß40 have opposing effects on amyloid deposition: Aß42 promotes amyloid deposition but Aß40 inhibits it. In addition, increasing Aß40 levels protected BRI-Aß40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Aß40 with respect to amyloid deposition suggest that strategies that preferentially target Aß40 may actually worsen the disease course and that selective increases in Aß40 levels may actually reduce the risk for development of AD.
Key words: Alzheimer's disease; amyloid ß; aggregation; premature death; transgenic mice; cerebral amyloid angiopathy
Received Nov. 7, 2006; accepted Dec. 10, 2006.
Correspondence should be addressed to Dr. Eileen McGowan, Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224. Email: mcgowan.eileen{at}mayo.edu
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