More surprisingly, Cotel and co-workers have recently found that environmental enrichment has no effect on Ab load in APP/PS1KI mice. The conflicting findings might be attributed, at least partially, to the use of different transgenic models of AD. Our finding together with the those of Lee et al may confirm the AbMole Citiolone hypothesis that interactions between environmental risk factors and genetic background may influence the onset and progression of sporadic AD. It has also been shown that effect of behavioral stress on betaamyloidogenesis is sex-specific. Devi et al reported that behavioral stress increased plaque burden in the hippocampus of female 56FAD mice but not in the male 56FAD mice. However, the difference between our findings and those of Devi et al cannot be attributed to the difference in gender as we only used TgCRND8 female mice to evaluate the effect of restraint stress on Ab pathology. Our present study which showed the restraint stress failed to accelerate the onset and progression of Ab pathology in TgCRND8 does not necessarily mean that our results are conflict with the clinical observations that stress may be an important contributor to the onset and development of AD. Indeed, amyloid is only one part of a multi-factorial disease processes of AD incorporating a wealth of disease-causing factors. Under certain circumstances, factors that either aggravate or attenuate AD-like pathology may not act via Ab-related mechanisms. For example, Jeong et al have found that in their stress system, memory function was impaired under stress even though Ab deposition was unchanged. Similarly, Jankowsky et al have shown that environment enrichment has a protective effect on cognitive function regardless of exacerbation in Ab deposition. Our results provide evidence to support the notion that plaque load per se may not represent a significant outcome measure for evaluating the therapeutic effect on AD patients. It is worth mentioning that the psychological and physiological changes associated with restraint appear to result from the distress and aversive nature of having to remain immobile, rather than immobilization itself. In our study, we observed that restrained animals kept struggling even in a restrainer with a very limited space. The struggling of the mice increased, in a sense, physical activity. If so, this might explain why the restraint stress failed to aggravate the Ab pathology in TgCRND8 mice, for it has been shown that higher levels of physical activity can attenuate Ab pathology. The physical activity might counteract the effect of the psychological stress on Ab pathology in the present study. The evidence that increased physical activity as well as enriched housing can reverse the effect of stress on the progression of AD in a mouse model of AD also lend support to the above explanation. The implication of our findings is that even if we constantly experience various types of stress, some forms of effective interventions, e.g, increasing physical activity, can always be applied to confront and offset the adverse effects of stress on the onset and progression of AD pathology. Serotonin transporter is coded by a single gene, which is located in human chromosome 17q11.2. After the discovery of polymorphism of the promoter region of the 5-HTT gene, with longer allele having higher basal and induced transcription rates than shorter.