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What are the biological mechanisms underlying the interaction between epilepsy and Alzheimer’s?
Fabio Antonio Borges Vigil, Ph.D.
University of Texas Health Science Center
San Antonio, TX - United States
Background
As many as 20 percent of individuals living with Alzheimer's experience brain seizures. These seizures resemble those experienced by individuals with epilepsy, and they can have both immediate and long-lasting effects on brain function. For example, individuals who have Alzheimer's and seizures experience more rapid declines in brain function than individuals with Alzheimer's but no seizures.
The protein fragment beta-amyloid has long been studied as a key hallmark brain change in Alzheimer’s. Beta-amyloid tends to accumulate into clumps called plaques, which may hinder nerve cell communication in the brain and lead to brain cell death. Beta-amyloid is produced from a larger molecule, amyloid precursor protein (APP), in a two-stage process. The first stage involves an enzyme (or cutting protein) called beta-secretase 1 (BACE1).
Though the exact mechanisms by which seizures affect cognition are unknown, evidence suggests that the activity of "channels" (or molecular pathways) through which nerve send electrical communication signals becomes altered. These alterations may lead to a harmful process called excitotoxicity, in which nerve cells become overstimulated and damaged.
When BACE1 binds to specific potassium channels, it ultimately leads to a decrease in seizure activity. Dr. Fabio Borges Vigil and colleagues believe that the availability of APP regulates the binding of BACE1 to potassium channels, and that this interaction may play a role in Alzheimer’s-related seizure activity and progression of the disease.
Research Plan
Dr. Vigil and colleagues will study whether APP activity regulates BACE1 binding to potassium channels in nerve cells from genetically engineered Alzheimer’s-like mice. Next, the team will investigate how APP may regulate BACE1 binding to potassium channels in genetically engineered mouse models of Alzheimer’s that develop seizures. They will examine brain and seizure activity, learning and memory, and Alzheimer’s-related brain changes in these mice and cognitively unimpaired mice.
Impact
The results may shed light on the mechanisms underlying the interaction between Alzheimer’s and epilepsy and may eventually lead to new therapeutic strategies that target these mechanisms.
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