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The Journal of Neuroscience, January 6, 2010, 30(1):372-381; doi:10.1523/JNEUROSCI.5341-09.2010

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Neurobiology of Disease
Many Neuronal and Behavioral Impairments in Transgenic Mouse Models of Alzheimer's Disease Are Independent of Caspase Cleavage of the Amyloid Precursor Protein

Julie A. Harris,^1,2 * Nino Devidze,^1 * Brian Halabisky,^1,2 Iris Lo,¹ Myo T. Thwin,¹ Gui-Qiu Yu,¹ Dale E. Bredesen,^2,3 Eliezer Masliah,⁴ and Lennart Mucke^1,2

¹Gladstone Institute of Neurological Disease and ²Department of Neurology, University of California, San Francisco, San Francisco, California 94158, ³Buck Institute for Age Research, Novato, California 94945, and ⁴Departments of Neurosciences and Pathology, University of California, San Diego, San Diego, California 92093

Correspondence should be addressed to Dr. Lennart Mucke, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: lmucke{at}gladstone.ucsf.edu

Previous studies suggested that cleavage of the amyloid precursor protein (APP) at aspartate residue 664 by caspases may play a key role in the pathogenesis of Alzheimer's disease. Mutation of this site (D664A) prevents caspase cleavage and the generation of the C-terminal APP fragments C31 and Jcasp, which have been proposed to mediate amyloid-β (Aβ) neurotoxicity. Here we compared human APP transgenic mice with (B254) and without (J20) the D664A mutation in a battery of tests. Before Aβ deposition, hAPP–B254 and hAPP–J20 mice had comparable hippocampal levels of Aβ_1-42. At 2–3 or 5–7 months of age, hAPP–B254 and hAPP–J20 mice had similar abnormalities relative to nontransgenic mice in spatial and nonspatial learning and memory, elevated plus maze performance, electrophysiological measures of synaptic transmission and plasticity, and levels of synaptic activity-related proteins. Thus, caspase cleavage of APP at position D664 and generation of C31 do not play a critical role in the development of these abnormalities.

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Received Oct. 28, 2009; accepted Nov. 2, 2009.

Correspondence should be addressed to Dr. Lennart Mucke, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: lmucke{at}gladstone.ucsf.edu

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