科研之友
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摘要
The J20 mouse expresses human mutant amyloid-beta protein precursor (hA beta PPSwInd) and is an established transgenic model of Alzheimer's disease (AD). From the age of 5 months, amyloid-beta (A beta) deposits appear in the hippocampus with concomitant increase of AD-associated features. Although changes occurring after the appearance of A beta deposits have been extensively studied, very little is known about alterations that occur prior to 5 months. The present study aimed to identify changes in the cellular composition and proliferative potential of the J20 hippocampus using 1-18-month-old mice. Neuronal, non-neuronal, Ki-67+, and TUNEL+cell numbers were counted with the isotropic fractionator method. Age-dependent changes of the expression of microglia-, astrocyte-, and neurogenesis-specific markers were sought in the entire hippocampus. Several transgene-associated changes were revealed before the appearance of A beta deposits. The number of proliferating cells decreased whereas the number of microglia clusters increased as early as 4 weeks of age. The neurogenesis was also impaired in the dentate gyrus of 7-11-week-old J20 mice. A statistically significant negative correlation was found between the number of proliferating cells and age in both populations, but the time course of the age-dependence was steeper in wild-type than in J20 mice. Negative age-dependence was noted when the number of cells committed to apoptosis was examined. Our results indicate that overexpression of mutant hA beta PP initiates a cascade of pathologic events well before the appearance of visible A beta plaques. Accordingly, early signs of AD include reduced cell proliferation, impaired neurogenesis, and increased activity of microglia in the hippocampus.
- 出版日期2014
