Gene-environment interaction research and transgenic mouse models of Alzheimer's disease

Abstract

The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.

Figure 1

Research in Alzheimer's disease (AD) uses both clinical (human) and preclinical (mouse) methods to elucidate the underlying mechanisms of AD etiology. Epidemiological findings such as genetic and environmental risk factors can provide tools for investigating their effects on AD etiology separately in mouse models of AD. In this paper it is, however, postulated that AD research should move towards a gene-environment (GxE) interaction approach, so that the synergistic participation of genes and environment can be scrutinized. Genes in the dashed box represent those genes found to be implicated with Alzheimer's disease etiology in humans, while genes in the solid box resemble the genes that are currently used in mouse models of Alzheimer's disease. APOE4: Apolipoprotein ε4; APP: amyloid precursor protein; CLU: clusterin; EMF: electromagnetic field; PICALM: phosphatidylinositol-binding clathrin assembly protein; PS1: Presenilin 1; PS2: Presenilin 2.