Systems Genetics of Normal Aging and Alzheimer's Disease.
Although aging is the most important risk factor for AD, it remains unclear to what extent the molecular changes that underlie ‘normal’ age-associated memory deficits contribute to symptoms of dementia observed in patients with sporadic AD. This is likely due to individual differences in the aging process, where the risk and severity of developing sporadic AD depends on complex genetic interactions that are influenced by environmental factors. Recently my colleagues and I demonstrated that spatial memory deficits in mouse models of ‘normal’ aging and AD correspond to changes in the excitability of neurons of the hippocampus, which others have shown depends on the genetic background strain(Moore et al., 2011). This project is focused on identifying the complex genetic factors that underlie individual differences in memory function in aged mice using a new integrative systems genetics approach.
In Aim 1, quantitative trait loci (QTLs) and candidate genes will be identified that associate with memory function across a large family of genetically diverse murine lines (the DO and CC mouse panels) at 10-46 mo. The DO and CC panels were specifically designed to model genetically admixed human populations, and for that reason, are well suited to identify complex genetic influences on memory with high translational potential. The functional relevance of candidate genes and/or networks will be linked to cellular mechanisms using biophysical assays in vitro, and directly tested in loss and gain of function experiments in vivo using established methods beyond the award phase. The translational relevance of candidate genes will be tested for associations with available data from human cohorts.