How the ApoE4 protein increases the brain’s susceptibility to Alzheimer’s disease remains unknown. We do know that as the protein circulates in the blood, it helps to regulate cholesterol levels and protect against vascular disease. ApoE is also produced in the brain, where it is involved in clearing away beta-amyloid as well as regulating the transport of cholesterol. Animal studies are also uncovering roles for ApoE and other proteins in the development and function of synapses, the tiny structures that connect neurons and enable them to communicate with each other.
Scientists at Georgetown University in Washington, DC, and Duke University in Durham, NC, discovered abnormalities in the synaptic development in mouse models carrying the APOEε4 allele even before the mice reached puberty. Their neurons had fewer dendrites, the branch-like structures that receive messages from other neurons, than those of APOEε3 or APOEε2 model mice (Dumanis et al., 2009). This was associated with less synaptic activity in the amygdala, a brain region important for emotional memory (Klein et al., 2010). In both cases, the deficits were already evident at 1 month of age and progressed as the mice grew older. These studies suggest that while the impact of APOEε4 on cognition is not apparent until later in life, its presence may be harmful to the structure and function of neurons much earlier.
Conversely, the APOEε2 allele associated with decreased risk for Alzheimer’s in humans appears to promote synaptic development and, presumably, synaptic function in mice. The neurons of young APOEε2 mice had longer and more elaborate dendrites and as a result, more synaptic contacts than those of APOEε3 or APOEε4 model mice.
The protein ApoE4 may impair synaptic plasticity, or the ability of synapses to weaken or strengthen connections to other synapses—a function critical to learning and memory. When investigators from the University of Texas Southwestern Medical Center added the protein to mice brain segments in the lab, it interfered with the usual chain of cellular responses critical to plasticity, including activity of the protein Reelin, which is involved in plasticity and neuronal function (Chen Y et al., 2010). It particularly affected LTP. This finding could explain the decline in synaptic function seen in both MCI and Alzheimer’s disease and suggests a possible target for therapeutic intervention.
What is LTP?
LTP, or long-term potentiation, is a process used in research settings to stimulate by mechanical means the connections between neurons in slices of animal brains. LTP studies have shown that the stronger the connection, the better the neurons are able to relay messages across synapses. Researchers theorize that LTP may play a role in learning and memory, but this experimental model has yet to be proved in animals or humans.