The ε4 allele of human APOE gene is the greatest genetic risk factor for AD. While the mechanisms underlying this effect remain unclear, current evidence supports both an impaired function of apoE4 in supporting brain lipid metabolism and synaptic integrity, as well as gain-of-toxic-function in promoting Aβ accumulation. Thus, the overall goal of this PPG is to understand the basic biology and the pathogenic pathways of the apoE isoforms and apoE receptors. In the past five years, the PPG laboratories have made remarkable progress toward our goal, partially reflected in >100 publications. We have demonstrated that apoE4 is associated with lipoproteins and less likely to form apoE/Aβ complexes than apoE3. This results in more "free" Aβ that can aggregate to form toxic Aβ oligomers. Using in vivo studies with transgenic mice, we found that APOE genotype affected the type and amount of Aβ deposition, as well as the glial-mediated inflammatory response to Aβ. In studies of Aβ-independent pathways, we found that APOE4 significantly impaired spatial learning and memory in human APOE-targeted replacement mice, likely a result of its impaired function in supporting dendrites and synapses. In the area of apoE receptor biology and pathobiology, we generated conditional knockout mouse models of a major apoE receptor, LRP1, and demonstrated a critical role for this receptor in both supporting brain lipid transport and synaptic plasticity, and in promoting Aβ clearance by brain parenchymal cells and the cerebral vasculature. We have also dissected the signaling pathways of the apoE receptors VLDLR and ApoER2. In addressing human relevance, we have systemically analyzed the genetic association of apoE receptors and related genes with AD, identifying new effects of polymorphisms on mRNA splicing and levels of gene expression. Using post-mortem brain samples, we have also established relationships between the expression levels of apoE and apoE receptors with AD-related pathology.
In addressing apoE-related pathways, we have generated critical evidence supporting interplay between APOE4, neuroinflammation and glucose metabolism. Thus, we have entered a new phase of this PPG with an overall hypothesis that APOE4 promotes a chronic neuroinflammatory state and impaired glucose metabolism with aging, leading to increased risk of Alzheimer's disease pathogenesis. For the next five years, our plan is to dissect apoE effects on receptor/pathway interactions that modulate neuroinflammation, insulin signaling and glucose metabolism. At present, there is little consensus as to the role or regulation of these receptors and signaling pathways, or subsequent functional effects in AD. Thus, until underlying mechanistic pathways are defined, identification of novel therapeutic targets is limited. We will address critical gaps in our scientific knowledge that prevent these intersecting pathways from being translated into therapeutic targets. Specifically, the four Projects and three Cores propose to test the innovative mechanism via: 1. Neuroinflammation is a complex phenotype that imparts specific functional phenotypes that can be classified as inflammotoxic, pro-inflammatory, anti-inflammatory, repair and immunoregulatory, as well the specific microglial states: M1-cytotoxic, M2A-alternative repair and M2B-deactivating, which we define as the "inflammatome". APOE4, through modulation of inflammatory receptors and pathways, induces an adverse inflammatome that: 2. activates inflammatory receptors on neurons to impair insulin signaling. In addition, apoE and LRP1 directly interact with neurons, such that the beneficial effects of LRP1 on insulin signaling are decreased by apoE4. 3. Impaired insulin signaling in neurons results in lower glucose transporter expression and deficits in glucose metabolism. Compared to apoE3, apoE4 directly impairs glucose utilization in astrocytes, further exacerbating neuronal glucose utilization. This global mechanism is exacerbated by Aβ and aging.
This PPG engages the scientific community by organizing annual APOE symposia sponsored by Core A. This symposium, in its 5th year in 2014, provides a platform for scientists to share their latest findings and identify potential collaboration opportunities. We also share a number of critical reagents for studies of apoE and apoE receptors with the broader scientific community, a service provided by Core B. Our ultimate goal is to establish novel targets for AD therapy by defining the critical mechanisms underlying apoE-related disease pathways.