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The Journal of Neuroscience, April 15, 2009, 29(15):4964-4971; doi:10.1523/JNEUROSCI.4560-08.2009

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Neurobiology of Disease
Suppression of Amyloid Deposition Leads to Long-Term Reductions in Alzheimer's Pathologies in Tg2576 Mice

Rachel A. Karlnoski,¹ Arnon Rosenthal,² Dione Kobayashi,² Jaume Pons,² Jennifer Alamed,¹ Mary Mercer,¹ Qingyou Li,¹ Marcia N. Gordon,¹ Paul E. Gottschall,¹ and David Morgan¹

¹Alzheimer's Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, University of South Florida, Tampa, Florida 33612, and ²Rinat Laboratories, Pfizer, South San Francisco, California 94080

Correspondence should be addressed to David Morgan, Alzheimer's Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Services, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC Box 9, Tampa, FL 33612. Email: scientist.dave{at}gmail.com

In amyloid precursor protein (APP) models of amyloid deposition, the amount of amyloid deposits increase with mouse age. At a first approximation, the extent of amyloid accumulation may either reflect small excesses of production over clearance that accumulate over time or, alternatively, indicate a steady-state equilibrium at that age, reflecting the instantaneous excess of production over clearance, which increases as the organism ages. To discriminate between these options, we reversibly suppressed amyloid deposition in Tg2576 mice with the anti-Aβ antibody 2H6, starting at 8 months, just before the first histological deposits can be discerned. Six months later, we stopped the suppression and monitored the progression of amyloid accumulation in control APP mice and suppressed APP mice over the next 3 months. The accumulation hypothesis would predict that the rate of amyloid from 14 to 17 months would be similar in the suppressed and control mice, while the equilibrium hypothesis would predict that the increase would be faster in the suppressed group, possibly catching up completely with the control mice. The results strongly support the accumulation hypothesis, with no evidence of the suppressed mice catching up with the control mice as predicted by equilibrium models. If anything, there was a slower rate of increase in the suppressed APP mice than the control mice, suggesting that a slow seeding mechanism likely precedes a rapid fibrillogenesis in determining the extent of amyloid deposition.

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Received Sept. 23, 2008; revised Oct. 15, 2008; accepted Feb. 13, 2009.

Correspondence should be addressed to David Morgan, Alzheimer's Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Services, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC Box 9, Tampa, FL 33612. Email: scientist.dave{at}gmail.com

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