2023 Alzheimer's Association Clinician Scientist Fellowship (AACSF)
What is the Role of Axonal Degeneration in Ischemia-Triggered Dementia?
How may damage to communication-related nerve cell extensions promote dementia risk after undergoing a stroke?
Jack Wang, M.D., Ph.D.
Stanford University School of Medicine
Stanford, CA - United States
Background
Blood flow into our brain is essential for the brain to function effectively. Impaired blood flow can lead to lower oxygen levels, also known as “ischemia,” in the brain, a problem that may result in stroke. Ischemic stroke, in turn, can increase one’s risk for cognitive decline and dementia. Research has found that ischemic stroke may increase the risk of dementia by triggering the body’s immune system to become chronically overactive – though the mechanisms underlying this link between stroke and immune system impairment remain unknown.\\
In initial studies with genetically engineered mice, Dr. Jack Wang and colleagues found that ischemic stroke damages axons (the long, thread-like extensions that nerve cells use to communicate with each other), and that such damage is primarily responsible for the chronic immune activity that leads to post-stroke dementia. Moreover, they found that dementia-related axonal damage is related to impairments in an immune system enzyme (or cutting protein) called sterile alpha and TIR motif containing 1 (Sarm1).
Research Plan
The researchers will now analyze genetically engineered mice with or without Sarm1. After inducing ischemic stroke in the mice, they will determine how the presence or lack of Sarm1 impacts axonal damage, and how this damage may lead to immune system dysfunction and cognitive decline.
Impact
Dr. Wang’s study will shed new light on the mechanisms underlying post-stroke dementia. It could also lead to novel methods for preventing this type of dementia by targeting Sarm1.