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Nature Medicine  4, 97 - 100 (1998)

Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes

Leigh Holcomb1, Marcia N. Gordon1, Eileen McGowan2, Xin Yu2, Stan Benkovic1, Paul Jantzen1, Kristal Wright1, Irene Saad1, Ryan Mueller1, 5, Dave Morgan1, Sunny Sanders2, Cindy Zehr2, Kassandra O'Campo2, John Hardy3, Cristian-Mihail Prada4, Chris Eckman4, Steve Younkin4, Karen Hsiao5 & Karen Duff2

  1Alzheimer's Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, Florida 33612, USA

  2Neurotransgenics Laboratory, Mayo Clinic, Jacksonville, Florida 32224, USA email

  3Neurogenetics Laboratory, Mayo Clinic, Jacksonville, Florida 32224, USA

  4Molecular Neuropathology Laboratory, Mayo Clinic, Jacksonville, Florida 32224, USA

  5Department of Neurology, University of Minnesota, UMHC Box 295, 420 Delaware Street, Minneapolis, Minnesota 55455, USA

 Correspondence should be addressed to K.D.; e-mail

 Correspondence regarding behavior and pathology methodlogy be addressed to D.M. L.H. and M.N.G contributed equally to this work.

Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (P52) genes1. The mutant APP K670N,M67M transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (AP) levels at an early age and, by 9−12 months, develops extracellular AD-type Ap deposits in the cortex and hippocampus2. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide Abeta342(43) (ref. 3). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1 M46L transgenic line develop large numbers of fibrillar Abeta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 litter-mates. In the period preceding overt Abeta deposition, the doubly transgenic mice show a selective 41% increase in Abeta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a P51 mutation, which causes a modest increase in Abeta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial Abeta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.

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