Efficacy of NPI in the Rescue of γ-Secretase Activity Following Knockdown with RNAi Treatment
Glista, Michael J.
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Alzheimer’s disease is the leading cause of dementia and memory loss among the elderly. One in ten people over age 65 suffers from Alzheimer’s, and more than half of all people over 85 have the disease. Care for the disease is expensive – in America, it is the third most expensive disease, following heart disease and cancer, with an average lifetime cost of care per patient of $174,000. For the above reasons, the search for effective treatments and preventative measures for this disease is a high priority. At the cellular level, Alzheimer’s disease is linked to the enzymatic cleavage of a particular transmembrane protein, the amyloid precursor protein (APP), which results in the release of an ectodomain known as Aβ. Gamma-secretase, which is responsible for the transmembrane proteolysis of APP (Figure 1), is a complex of several proteins. Recently, the St. George-Hyslop lab has identified a novel protein (NP1) that may be required for regulation of this cleavage event, as suppression of NP1 production in vitro leads to elevated levels of secreted Aβ (Figure 2, Hasegawa, Unpublished). NP1 is a type I, transmembrane, trafficking-related protein that belongs to a family of proteins studied previously in the context of vesicular transport. Due to the observed elevation in secreted Aβ and the observation that NP1 co-precipitates with all known components of the γ- secretase complex, it is therefore possible that this protein has a role in the function of the γ-secretase complex, and, subsequently, in APP processing.