University of California, San Diego (UCSD)

Exploring The Link Between Increased APP And Neurodegeneration in Down Syndrome

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Our studies address the fact that all people with Down syndrome (DS) over the age of 40 show the pathological features of Alzheimer’s disease (AD). This remarkable finding points to the possibility that by understanding the changes in DS – changes that are highly predictable and can be studied over many years – we might gain unique insights into how the brain is affected in AD and learn how best to diagnose and treat this devastating condition.

Our special focus is on the possibility that defective delivery of trophic messages between cells plays an important role. We know a good deal about how these messages are communicated in the normal brain and have recently discovered that their delivery is markedly impaired in mouse models of DS and AD. In DS, the gene for APP is present in three copies, instead of the normal two. The same gene is mutated in some people with AD. Building on studies that pointed to increased APP protein levels induce a defect in the delivery of trophic signals, we proposed the hypothesis that changes in the synthesis or processing of APP inhibit transport of trophic signals, leading to neuronal dysfunction and degeneration in DS and AD. It is not known whether APP overexpression acts directly or indirectly to disrupt signaling traffic. Our experiments will pursue how it is that APP is involved and will demonstrate conclusively whether failed delivery of trophic signals is responsible for neuronal degeneration. Importantly, because we have the ability to examine a patient population that is uniformly destined to develop AD, we can test the feasibility of a novel set of tools to characterize disease onset and progression, raising the possibility that our studies can be used to define more precisely the cellular and molecular events that underlie the degeneration of critical neural circuits and to learn how to prevent or treat them early and effectively.