Alzheimer disease rages in the brain long before plaques form, and even before the earliest measurable cognitive symptoms. Most in the field agree that early interventions are the best hope of nipping memory loss and cognitive decline in the bud. Which raises the question—when exactly, and where, does AD start?
To find some answers, Floyd Bloom of Neurome Inc., and the Scripps Research Institute, both in La Jolla, California, has been scrutinizing young PDAPP mice, looking for the earliest signs of pathological change (see ARF related news story and ARF news story). Using morphological, behavioral, and biochemical measures, Bloom and colleagues have pinpointed defects in the hippocampus as early as 4-5 months of age in these mice, long before plaques appear at 18 months. Their goal is to define early changes in the mouse model as a testing ground for therapeutics, and to understand the early memory loss that occurs in people with AD.
The progression of AD varies among different mouse models, leading Bloom and colleagues to extend their analysis to another transgenic model, the Tg2576 mouse. In a paper in this week’s PNAS Early Edition, first author J. Steven Jacobsen at Wyeth Research in Princeton, New Jersey, and colleagues report that the Tg2576 mice undergo similar, but not identical changes at 4-6 months of age compared to the PDAPP mice. Like in the PDAPP mice, the first change seen was a decrease in spine density in the outer molecular layer of the dentate gyrus in the hippocampus by 4 months of age. But unlike earlier findings in the PDAPP mice, the researchers did not find a decrease in hippocampal volume in the Tg2576 line. The published work follows a presentation at last year’s Society for Neuroscience meeting (see ARF related news story).
The loss of dendritic spines observed at 4 months of age coincided with a decrease in basal synaptic transmission and long-term potentiation in hippocampal slices, as well as behavioral changes in the hippocampal-based learning test of contextual fear conditioning. The cause of these synaptic problems remains to be found. The researchers did detect a measurable rise in the fraction of soluble Aβ42 after 6 months, correlating with the emergence of spatial memory defects. It took a detailed analysis of soluble Aβ species by Karen Hsiao Ashe and colleagues to identify a specific dodecameric form of Aβ as a candidate for causing the memory problems that show up at 6 months in these mice (see ARF related news story), and the same type of analysis may be required to shed light on the even earlier events.
The decrease in spine density in the dentate gyrus in two different models suggests this may be a common early effect of aberrant APP processing, consistent with other studies that this region is highly sensitive to aging. If the early changes seen in the mouse model mimic the early memory defects in humans (as the authors deem likely), then the animals and techniques described will be valuable for testing early treatments.—Pat McCaffrey
- Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed.
- Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6. Epub 2006 Mar 20 PubMed.