Current Projects

Nematode Caenorhabditis elegans

At the UW ADRC, we are busy finding ways to identify, treat, and prevent Alzheimer’s disease. We tackle these challenges through the ongoing work of our cores, nationwide collaborative studies, and the five-year projects and one-year pilot award projects, each of which attempts to contribute to our understanding of Alzheimer's disease in new and innovative ways.

ADRC Projects

Project 1

Title: Mechanisms Linking Normative Aging with Alzheimer’s Disease

Project leader: Dr. Matt Kaeberlein,  Professor, Department of Pathology, University of Washington

Age is the single greatest risk factor for Alzheimer’s disease, yet the way in which normal aging processes differ from those processes that lead to Alzheimer’s isn’t entirely clear. This project seeks to understand the molecular processes that cause cells to become more susceptible to Alzheimer’s by studying aging roundworms known as nematode Caenorhabditis elegans (C. elegans). Using the nematode model, we will determine the effects of toxic amyloid-beta on gene expression in the context of normal aging. Then, we will explore how two important signaling pathways, the hypoxic response and the mechanistic target of rapamycin (mTOR), modulate cellular resistance to amyloid-beta toxicity. Previously, the Kaeberlein Lab has shown that both of the pathways regulate normal aging and resistance to amyloid-beta in C. elegans. These studies are likely to provide novel insights into the relationship between normal aging and AD with the overall aim of developing therapies that will delay the onset and progression of Alzheimer’s.

Project 2

Title: Rationally designed modulators of the amyloid-beta aggregation cascade

Project leader: Dr. David Baker, Professor, Department of Biochemistry, University of Washington, and Investigator, Howard Hughes Medical Institute

The accumulation of abnormally folded amyloid-beta proteins is widely accepted as the root cause of Alzheimer’s disease, but researchers have had difficulty developing medications that counteract these misfolded proteins. In this Project, we will use advanced computing techniques to design proteins and peptides that can alter these harmful processes, preventing the toxic amyloid-beta proteins from abnormally folding and accumulating in the brain. These artificially created peptides and proteins will be useful for developing new AD treatment strategies.

Project 3

Title: Dynamic Functional Connectivity MRI in Preclinical AD

Project leader: Dr. Thomas Grabowski, Professor, Departments of Radiology and Neurology, University of Washington, and Director, Integrated Brain Imaging Center, University of Washington

Imaging studies have identified altered functional connectivity in what is known as the default mode network (DMN) as a marker of preclinical Alzheimer’s disease. However, it is unclear how likely these changes are to predict Alzheimer’s-related memory decline, particularly in contrast to the dementia caused by cerebral microvascular disease as indicated by autopsy. Indeed, the Adult Changes in Thought (ACT) study, a community-based study of brain aging and incident dementia in the Seattle area, has demonstrated in large autopsy studies that the population-attributable risk of dementia in ACT was 45% from AD and 33% from cerebral microvascular disease. Therefore, using a cohort of ACT participants that is part of the UW ADRC Clinical Core (ACT-Plus), we will evaluate the specificity of DMN functional connectivity changes in preclinical AD, as well as MRI measures of the impact of cerebral microvascular disease. When successfully completed, this Project will have determined the utility of novel fMRI approaches to brain aging and preclinical AD in a sample that more closely reflects the ultimate target population.

 

►Find information about the UW ADRC Pilot Award projects and proposals here.