In this week's early online edition of PNAS, collaborative research directed by Floyd E. Bloom of Neurome Inc. and the Scripps Research Institute, both in La Jolla, California, shows that dramatic changes occur in the brains of mice expressing mutant human forms of AβPP long before any Aβ has been deposited. This study is the latest in an ongoing trend pointing to damage in young adult AD mouse models prior to amyloid plaque formation, fed to date primarily by electrophysiological and behavioral tests. It is also the first report of the use of quantitative three-dimensional MRI in an AD mouse model.
First author Jeffrey Redwine et al. examined mice expressing a mutant human AβPP originally found in cases of familial AD. Using high-resolution magnetic resonance microscopy, Redwine et al. measured the volume of different regions of mouse brains at various stages of growth. At 40 days of age, the authors found no difference between wildtype mice and their transgenic littermates, indicating that embryonic and early postnatal development are unaffected by mutant APP overexpression. Already by 100 days (i.e., young adulthood), however, the transgenic mice had a 12 percent reduction in hippocampal volume. The authors found this reduction to persist unchanged until 21 months. Intriguingly, it appears to result from poorer hippocampal growth because the hippocampi in wildtype mice actually grew by about 18 percent between 40 days and 21 months. There was no growth difference between wildtype and transgenic cerebellums, but the corpus callosum was about 25 percent shorter in transgenic mice of all ages.
The stunted hippocampal growth was most evident in the molecular layer of the dentate gyrus, the projection area of the perforant pathway that is severely affected early on in human AD. The researchers could not distinguish whether the loss in the dentate gyrus results from loss of projection neurons or resident dendrites, or both.
One surprise of this study was that the hippocampus apparently continues to grow in normal adult mice. Another was that volumetric losses in the transgenic animals preceded any detectable deposition of Aβ. This leads Redwine et al. to speculate that the mutant AβPP may cause early pathologic changes that slow down normal growth of the hippocampus. Among possible culprits, the authors mention increased soluble Aβ, citing its reported ability to bind to neuronal receptors and to agrin, a protein known to function in dendritic growth and synapse formation. Finally, the authors write that their findings reinforce the importance of developing strategies to detect AD early; one of the promising candidates for this goal is measuring the volume of the hippocampus and other selected brain regions by MRI. This study also suggests that prospective imaging studies of FAD family members even in their twenties may yield valuable insight into the natural history of this disease.—Tom Fagan and Gabrielle Strobel
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- Redwine JM, Kosofsky B, Jacobs RE, Games D, Reilly JF, Morrison JH, Young WG, Bloom FE. Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: a magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1381-6. PubMed.