2004 Investigator-Initiated Research Grant

Nerve cells communicate by sending and receiving messenger chemicals across tiny gaps called synapses. Memory formation may depend, in part, on a phenomenon called long-term potentiation (LTP), a kind of “increased sensitivity” that develops with repeated sending and receiving of a message across a synapse. In Alzheimer’s disease, a tiny protein fragment called beta-amyloid may impair LTP, thereby causing or contributing to memory deficits associated with the disease.

Barbara Trommer, M.D., and colleagues are investigating how a genetic susceptibility to Alzheimer’s disease may influence this toxic effect on brain cell function. APOE is a gene found most commonly in three forms: APOE-e2, APOE-e3, and APOE-e4. The e4 version is associated with an increased risk of developing Alzheimer’s disease, and the e2 version with a decreased risk.

In previous research, the investigators studied mice that are genetically altered to carry human APOE genes and that develop an Alzheimer-like disorder. They found that APOE-e4 mice were, as expected, more susceptible to beta-amyloid–associated impairment of LTP. APOE-e3 mice had intermediate susceptibility, and e2 mice were resistant to LTP impairment.

In this study, the researchers are expanding this inquiry by assessing how these factors are influenced by age and gender. They will test LTP function in young-adult and middle-aged, male and female mice that carry one of the three forms of the gene. They will also study changes in cell-to-cell communication that may reveal exact processes by which beta-amyloid affects LTP. The outcome of this work may help explain the complex interaction of disease-related factors and suggest new therapeutic strategies.