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(American Journal of Pathology. 2000;157:331-339.)
© 2000 American Society for Investigative Pathology

Animal Model

Age-Related Amyloid ß Deposition in Transgenic Mice Overexpressing Both Alzheimer Mutant Presenilin 1 and Amyloid ß Precursor Protein Swedish Mutant Is Not Associated with Global Neuronal Loss

Ayano Takeuchi*, Michael C. Irizarry{dagger}, Karen Duff{ddagger}, Takaomi C. Saido§, Karen Hsiao Ashe, Masato Hasegawa*, David M. A. Mann||, Bradley T. Hyman{dagger} and Takeshi Iwatsubo*

From the Department of Neuropathology and Neuroscience,*
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; the Alzheimer Disease Research Unit,{dagger}
Massachusetts General Hospital, Charlestown, Massachusetts; the Nathan Kline Institute,{ddagger}
New York University, Orangeburg, New York; the Laboratory for Proteolytic Neuroscience,§
Brain Science Institute, RIKEN, Wako, Japan; the Center for Clinical and Molecular Neurobiology,
Departments of Neurology and Neuroscience, the University of Minnesota, Minneapolis, Minnesota; and the Department of Pathological Sciences,||
the University of Manchester, Manchester, United Kingdom

To analyze the relationship between the deposition of amyloid ß peptides (Aß) and neuronal loss in transgenic models of Alzheimer’s disease (AD), we examined the frontal neocortex (Fc) and CA1 portion of hippocampus (CA1) in PSAPP mice doubly expressing AD-associated mutant presenilin 1 (PS1) and Swedish-type mutant ß amyloid precursor protein (APPsw) by morphometry of Aß burden and neuronal counts. Deposition of Aß was detected as early as 3 months of age in the Fc and CA1 of PSAPP mice and progressed to cover 28.3% of the superior frontal cortex and 18.4% of CA1 at 12 months: ~20- (Fc) and ~40- (CA1) fold greater deposition than in APPsw mice. There was no significant difference in neuronal counts in either CA1 or the frontal cortex between nontransgenic (non-tg), PS1 transgenic, APPsw, and PSAPP mice at 3 to 12 months of age. In the PSAPP mice, there was disorganization of the neuronal architecture by compact amyloid plaques, and the average number of neurons was 8 to 10% fewer than the other groups (NS, P > 0.10) in CA1 and 2 to 20% fewer in frontal cortex (NS, P = 0.31). There was no loss of total synaptophysin immunoreactivity in the Fc or dentate gyrus molecular layer of the 12-month-old PSAPP mice. Thus, although co-expression of mutant PS1 with Swedish mutant ßAPP leads to marked cortical and limbic Aß deposition in an age-dependent manner, it does not result in the dramatic neuronal loss in hippocampus and association cortex characteristic of AD.




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