Beta Amyloid Regulation of Presynaptic Nicotinic Current

This project is aimed at understanding the physiological role of Amyloid beta. Using a defined nerve cell system in culture, we can express target protein receptors for beta amyloid and then examine the functional consequence via several techniques. We can also introduce mutations into the receptors or make deletions to define precisely the molecular components targeted by beta amyloid. Finally, we can explore derivatives of beta amyloid as potential means to disrupt beta amyloid’s action.

Alzheimer’s disease is a relentlessly progressive degenerative disorder for which there is currently only limited treatment. Early in the disease memory deficits occur, followed later by disruption of many facets of thinking and even language. Eventually, patients can no longer recognize anyone, including family members, and cannot care for themselves. Thus, it would appear that the disease results from a number of brain functions going awry at different times over its course, involving multiple pathological entities. One entity in particular is a small, sticky peptide known as beta amyloid, which accumulates in the brains of aging adults and eventually forms large, dense deposits (otherwise known as plaques). What free beta amyloid is doing in the brain in the first place is completely unknown, but its accumulation into deposits is one of the first signs in the course of the disease. It is largely produced from nerve endings where they make contacts with and signal to other nerve cells. Normally, this signaling from nerve endings to nerve cells is the primary way that communication occurs within the brain and we are hypothesizing that the free beta amyloid, accumulated at pathological levels, disrupts this basic communication. At present, one particular hope is to identify individuals at risk for heavy accumulation of the beta amyloid, using brain imaging techniques, and then to remove the free beta amyloid. In animal models where beta amyloid is artificially expressed in the brain, early removal of accumulating free beta amyloid prevents the memory deficits that result from the presence of beta amyloid; however, removal from the brain has required vaccination against beta amyloid and to date that has been problematic, though still remains an important and hopeful avenue. Another approach is to disrupt beta amyloid’s pathological actions, potentially preserving its normal function. In order to address this idea, it is essential to understand beta amyloid’s normal function. This project is aimed at understanding its physiological role. Using a defined nerve cell system in culture, we can express target protein receptors for beta amyloid and then examine the functional consequence via several techniques. We can also introduce mutations into the receptors or make deletions to define precisely the molecular components targeted by beta amyloid. Finally, we can explore derivatives of beta amyloid as potential means to disrupt beta amyloid’s action.

Grantee institution at the time of this grant: Drexel University