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The Journal of Neuroscience, October 4, 2006, 26(40):10129-10140; doi:10.1523/JNEUROSCI.1202-06.2006

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Neurobiology of Disease
Intraneuronal -Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

Holly Oakley,¹ Sarah L. Cole,¹ Sreemathi Logan,¹ Erika Maus,¹ Pei Shao,¹ Jeffery Craft,¹ Angela Guillozet-Bongaarts,¹ Masuo Ohno,² John Disterhoft,² Linda Van Eldik,¹ Robert Berry,¹ and Robert Vassar¹

Departments of ¹Cell and Molecular Biology and ²Physiology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Correspondence should be addressed to Dr. Robert Vassar, Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. Email: r-vassar{at}northwestern.edu

Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of -amyloid 42 (A₄₂) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce A₄₂ and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral A₄₂ levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase A₄₂ production. 5XFAD mice generate A₄₂ almost exclusively and rapidly accumulate massive cerebral A₄₂ levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal A₄₂ accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal A. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal A₄₂-induced neurodegeneration and amyloid plaque formation.

Key words: Alzheimer's disease; transgenic mice; A₄₂; amyloid plaques; intraneuronal A; neuron loss

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Received March 20, 2006; revised July 24, 2006; accepted Aug. 24, 2006.

Correspondence should be addressed to Dr. Robert Vassar, Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. Email: r-vassar{at}northwestern.edu

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