New Scholar Award in Aging
Jacob Raber, Ph.D.
Oregon Health & Science University

Gender and Isoform-Specific Effects of ApoE on Cognition in Humans

Our research focuses on the effects of genetic and environmental factors on brain function in experimental mouse models of human neurological diseases. Routinely, we use a combination of behavioral, neuroendocrine, and neurochemical approaches. Based on what we learn in the mouse models, we try to develop tests and treatment strategies to improve brain function in humans suffering from these diseases.

The three major human apolipoprotein (apo) E isoforms are encoded by distinct alleles (e 2, e 3, and e 4). Compared with e 2 and e 3, e 4 increases the risk of cognitive impairments and of developing Alzheimer’s disease (AD). ApoE4 interacts with female gender, resulting in an even greater risk of developing AD and in a diminished treatment response. ApoE4 might also be associated with an accelerated AD decline, but this remains controversial. Consistent with these human data, our data show that in transgenic mice expressing human apoE isoforms in the brain and lacking mouse apoE (Apoe-/-) female, but not male, apoE4 mice develop progressive impairments in spatial and nonspatial learning and memory, compared with age- and sex-matched wild-type, Apoe-/- or apoE3 mice. This could be relevant to cognitive impairments in human e 4 carriers. Because the cognitive impairments are observed in female apoE4 mice that express apoE4 in neurons or astrocytes, they are independent of the cellular source of apoE. Sex steroids might contribute to the gender-dependent effects of apoE4. Treatment with testosterone or dihydrotestosterone, a testosterone derivative that cannot be aromatized to 17-b estradiol, antagonizes the cognitive deficits of adult apoE4 female mice. In addition, adult apoE4 male mice, which do not show cognitive deficits in the water maze, develop them after blockade of androgen receptors, whereas apoE3 male mice do not.

We will develop virtual reality (VR) testing to bridge the gap between spatial learning and memory in healthy elderly and elderly with cognitive disorders and animal models of these illnesses. VR testing enables the use of paradigms similar to those used in animal studies and provides objective performance measures. In humans, spatial memory tests to assess visual-spatial memory are routinely used in which all the information is within one field of view and the subject has an aerial perspective and a body-centered (egocentric) frame of reference (table-top tests). Such tests are very different from spatial memory tests comparable to those used in rodents in which all the information is throughout a complex environment in which the subject navigates and has a viewer perspective and a word-centered (allocentric) frame of reference. In our VR setup, the subject sits in a motorized vehicle and is immersed in a computer-generated virtual world, through a head-mounted display (HMD) system comprised of special LCD video goggles and headphones, that changes with head and body motion. Inside the visor of the helmet are one video screen for each eye, generating a 3-dimensional experience, and two earphones presenting stereo sounds coinciding with the visual images. A transmitter on the HMD allows the computer to monitor changes in head position and to generate a corresponding point-of-view. Each back tire of the motorized vehicle is placed on its own set of rollers, allowing both wheels to move independently. Encoders built into the roller assembly enable the computer to determine the speed and direction of the motion. Using VR testing, we will assess interactions between apoE genotype and cognition in elderly males and females who are healthy, have mild cognitive impairment (MCI), or have AD. These studies will help to elucidate the roles of apoE isoforms in the brain. This is important for our understanding of cognitive function in health as well as in diseases characterized by cognitive impairments and will likely advance the development of therapeutic intervention to prevent or even reverse cognitive impairments.

Contact Dr. Raber.