2023 Alzheimer’s Association Leveraging Model & Data Resources to Advance Alzheimer’s and Dementia Discovery Program (ALZDISCOVERY)
Elucidating the Role of APOE Status on Neurovascular Coupling in ADRD
How may a gene variation linked to dementia risk promote Alzheimer’s-related changes in brain blood flow and energy production?
Paul Territo, Ph.D.
Indiana University
Bloomington, IN - United States
Background
The apolipoprotein E (APOE) gene provides instructions for making ApoE, a protein believed to help carry fats throughout the body. There are several genetic variations of APOE, including APOE-e3 and APOE-e4. Studies have shown that in some populations, individuals who possess APOE-e4 have an increased risk for developing Alzheimer’s disease and related dementia (ADRD), compared with individuals who have other APOE variants. However, the biological mechanisms that link APOE-e4 and dementia risk remain unclear.
In initial studies with genetically engineered mice, Dr. Paul Territo and colleagues found that mice with APOE-e4 have reduced metabolism (energy production) in the brain, as well as altered brain blood flow. These changes reveal problems with “neurovascular coupling,” or the body’s ability to provide sufficient blood flow to the brain to support healthy brain cell activity and energy levels. The researchers also found that mice with APOE-e4 had higher levels of an immune system molecule called Tumor Necrosis Factor Alpha (TNF-α). This molecule normally helps turn “on” immune cells to fight damage or infection in the body. However, excessive TNF-α has been shown to promote overactivity in immune cells, which may lead to abnormal blood flow and loss of energy production – changes that, in turn, can promote brain cell damage and memory loss characteristic of dementia.
Research Plan
Dr. Territo and colleagues will now work to clarify how APOE and TNF-α are linked to dementia-related blood flow and metabolism changes. They will develop mice that can be engineered to alter (or “switch”) the APOE variation they express throughout their brains. Some of the mice will be engineered to switch from APOE-e3 to APOE-e4 at around 4 months of age, while others will be developed to switch from APOE-e4 to APOE-e3 at the same age. The researchers will determine whether mice that switch to APOE-e4 experience greater TNF-α activity, reduced neurovascular coupling, and various other brain changes linked to dementia, such as beta-amyloid and tau protein clumping. Next, Dr. Territo’s team will conduct similar experiments with a second group of engineered mice that APOE switching will take place only in specific brain cells – helper cells called astrocytes and immune cells called microglia. The researchers will determine whether these cells play a primary role in APOE-related vascular and metabolic dysfunction.
Impact
Dr. Territo’s study could help clarify how the loss of vascular and metabolic health work together to promote dementia, and how APOE-e4 influences this process. The project could also lead to novel dementia therapies that target TNF-α.