Disterhoft -Physiology Department Subproject # SP0045610 Sporadic Alzheimer's Disease modeled with diabetes and high cholesterol in rabbit

This project concerns the etiological origins of sporadic Alzheimer’s disease (AD). While plaques and tangles still define AD, it is thought that oligomeric forms of Aβ and tau play major roles in the pathogenic mechanism. What triggers the buildup of these toxins, however, and whether the etiological triggers affect toxin impact, remain major unknowns. The long-term goal of this project therefore is to understand the etiological origins of sporadic AD, with a strategic focus on the pathobiology of AD risk factors. Its central hypothesis is that risk factors have in common an ability to stimulate pathogenic AβO buildup, but that each has its own signature with respect to the nature and clinical outcome of this buildup. The important relationship between risk factors and AβO pathobiology has not been studied before in appropriate, non-transgenic models. The immediate focus is on two metabolic AD risk factors: hypercholesterolemia (HypC) and type 2 diabetes (T2D). Investigations will address three aims and will provide results that test the central hypothesis and a prediction of potential diagnostic value. AIM 1 Determine the pathobiology that makes hypercholesterolemia and type 2 diabetes act as risk factors for sporadic AD. The working hypothesis is that the dysfunctional metabolic states of hyper-cholesterolemia and type II diabetes are AD risk factors because they promote the buildup of pathogenic AβOs. AIM 2 Establish a mechanistic principle to explain why AD manifests as heterogeneous phenotypes. The working hypothesis is that although the risk factors hypercholesterolemia and type 2 diabetes each promote buildup of the AD-linked neurotoxin AβO, there is an etiology-sensitive signature to that buildup that influences the cognitive outcome. AIM 3 Establish in vivo biomarkers that can diagnose the etiology-sensitive status of AβO neuropathology. The working hypothesis is that tandem imaging of brain AβOs and brain function will optimally diagnose AD in a manner that is etiology-sensitive. Rabbit will be used as a non-transgenic model. Pilot data show that substantial memory dysfunction is caused by diets associated with HypC and T2D. This dysfunction is linked to AβO buildup, and it manifests with an etiology-specific signature. New analytics will establish the impact of HypC and T2D on brain region-selective memory performance, functional and molecular MRI, AD-linked neuropathology, and buildup of oligomeric forms of Aβ. The approach is the first rigorous investigation into the onset of AβO pathobiology in an animal model unbiased by transgene expression. The expected outcome is establishment of a molecular mechanism to connect risk factors HypC and T2D to sporadic AD. Results are expected, moreover, to establish a platform for future studies into mechanisms of the now-burgeoning list of AD risk factors, to illustrate the significance of etiology in AD diagnosis and precision medicine, and to accelerate development of effective AD treatments and strategies for AD prevention.