Kenneth Mackie, M.D.
Indiana University
Indianapolis, Indiana

2006 Investigator-Initiated Research Grant

The unique abilities of the brain are mediated in large part by the ability of nerve cells to rapidly communicate and process signals across tiny connecting gaps, or synapses. Because synapses are so crucial, their function is tightly controlled by a variety of mechanisms including presynaptic receptors, proteins that control the release of neurotransmitters, or chemical messengers, from the synapse.

One family of presynaptic receptors is the endocannabinoid family. These receptors bind one type of neurotransmitter and control the release of other neurotransmitters from synapses in parts of the brain affected by Alzheimer's disease.

Kenneth Mackie, M.D., and colleagues have studied genetically altered mice with an Alzheimer-like disorder and found that the function and distribution of endocannabinoid receptors is altered even before the mice develop amyloid plaques, one of the hallmark abnormalities of Alzheimer's disease. The researchers suspect that these alterations in the endocannabinoid receptors may explain some of the deficits in brain function among people with Alzheimer's disease.

Dr. Mackie and colleagues plan to further explore the role of the endocannabinoid system in Alzheimer's using two different approaches. One approach involves studying how Alzheimer's disease has changed the distribution of endocannabinoid receptors in humans who have died in different stages of the disease. The other approach involves studies of the endocannabinoid system in genetically altered mice, in which the expression of beta-amyloid protein fragment (the main component of amyloid plaques) or elements of the endocannabinoid system have been altered.