During aging, brain cells accumulate oxidative injury that causes proteins to misfold and become unusable by the cell. The ubiquitin-proteasome system (UPS) plays a helpful role by degrading these dysfunctional proteins in cells. Disruption of the UPS may be an important link between aging, protein aggregation, and neurodegenerative disorders. However, an experimental system for studying UPS activity in neurons is needed in order to test therapeutics that rescue failing UPS activity.

Researchers at Brigham and Women’s Hospital are using neurons derived from induced pluripotent stem cells (iNs) generated from patients and healthy individuals as a highly controlled, rigorous model system for understanding cellular pathways that mediate neuropathogenesis directly downstream of genetic risk factors.

In Alzheimer’s & Dementia the team recently established this system to directly study person-specific UPS activity in neurons. They found that different genetic risk factors for Alzheimer’s disease converge on defective UPS activity in neurons and that this in turn affected the accumulation of tau. The authors are Yi-Chen Hsieh, PhD, MS, formerly a fellow in the Ann Romney Center for Neurological Diseases in the Department of Neurology, Tracy L. Young-Pearse, PhD, vice chair of Basic Neuroscience Research in the Department, and colleagues.

Methods

The researchers generated iNs from more than 50 individuals in the Religious Order Study or Memory and Aging Project (ROSMAP), a cohort started in the 1990s by David Bennett, MD of Rush University in Chicago. These cohorts are composed of Catholic nuns, priests, and monks across the United States (ROS) or older persons recruited from communities around the Chicago metropolitan area (MAP).

Upon enrollment, ROSMAP participants are cognitively unaffected and are primarily over age 65. They agree to annual physiological examinations and cognitive function tests and consent to donate their organs, including their brain, after death.

In this study, the researchers conducted proteomic profiling of the iNs and then examined basal UPS activity and tau accumulation in iNs across different genetic backgrounds.

Principal Results

The key findings were:

• The UPS is a molecular pathway in Alzheimer’s disease—iNs that showed lower expression of proteins involved in proteostasis were associated with genetic risk factors for late-onset AD and tau accumulation.
• Accumulation of tau reduced proteasome activity, and mild UPS inhibition induced accumulation of tau—suggesting a positive feedback loop in neurons supports tau accumulation following an initiation event.
• Neurons from different genetic backgrounds were differentially vulnerable to mild UPS insult with bortezomib (a proteasome inhibitor used in a clinical setting for cancer), resulting in differences in tau accumulation.
• Exposing the iNs to bortezomib significantly increased certain proteins involved in proteostasis that offset proteasome inhibition.

These findings may be useful to identify proteins that mediate the vulnerability of neurons to abnormal protein accumulation and could represent therapeutic targets and establish a system for examining person-specific responses to new therapies.