Gene-Pyrethroid Interaction in Alzheimer's disease

阿尔茨海默病（AD）是一种进行性神经退行性脑疾病

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease and the most common cause of dementia worldwide. An estimated 5.8 million Americans age 65 and older are currently living with AD. There is currently no cure for this disease. Age is the most important risk factor for AD, but there are many other factors, including environmental exposures and genetic are thought to play a profound role. However, none of them alone is the sole factor in disease development and progression. To date, a substantial amount of effort has focused on to identify genetic contributors to AD. Among the growing list of susceptibility genes, only the apolipoprotein E (APOE) has been identified as an individual strong contributor to AD. Apolipoprotein E4 (APOE4) allele is considered to be the highest contributor of genetic risk to late onset AD. Environmental exposure to toxic chemicals, including pesticides, are increasingly being recognized for their ability to increase the risk of AD. Patients with AD seriously suffer from cognitive deficits. The hippocampus is one of the most affected brain areas in AD and is a major regulator of cognitive function. Learning and memory deficits are associated with disruption of adult hippocampal neurogenesis in experimental animals and humans. Recent studies demonstrate adult hippocampal neurogenesis is reduced in patients with AD. Pyrethroid insecticides are one of the most widely used agricultural and household insecticides. Recently, we reported that repeated adult exposure to a relatively low dose of deltamethrin (3mg/kg) causes profound cognitive deficits in mice, which was accompanied by ER stress and marked impairment of hippocampal neurogenesis. Further, the APOE4 genotype has been associated with enhanced ER stress response and dysfunction of adult hippocampal neurogenesis. Here we will determine whether repeated exposure to deltamethrin and APOE genotype interact to cause enhanced ER stress, reduced hippocampal neurogenesis and worsened cognitive function associated with AD.