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Metabolon Extends Biochemical Understanding of Alzheimers Disease

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Metabolon, Inc., announces the publication of “Ablation of the Locus Coeruleus (LC) Increases Oxidative Stress in Tg-2576 Transgenic But Not Wild-type Mice” in the International Journal of Alzheimer Disease.

The paper examines the role of the LC on markers of oxidative stress in transgenic mice and was carried out as a collaboration among scientists at Pfizer, Proteostasis Therapeutics, the University of Dundee, Duke University and Metabolon. The paper is co-authored by Orest Hurko, Kurt Boudonck, Cathleen Gonzalez, J. Steve Jacobsen, Peter H. Reinhart, Crowther Daniel, Zoe A. Hughes.

Previous research in this area suggested that differences in inflammatory response observed in humans with Alzheimer disease and mouse models reflect a discrepancy in the state of the LC, the major site of norepinephrine synthesis in the brain. LC degeneration is an early change in human Alzheimer disease, but it is preserved in transgenic mouse models of Alzheimer disease.

The authors use a non-targeted metabolomic approach to examine the effects of ablating the LC on oxidative stress and intermediary metabolism. Mice transgenic for beta-amyloid (Tg2576Aß) in which the LC had been ablated showed greater concordance with human Alzheimer disease, including increased oxidative stress and altered energy metabolism.

The results support the proposal that LC degeneration may contribute to key pathophysiological features of Alzheimer disease, and extend the hypothesis from inflammation to oxidative stress and altered carbohydrate metabolism. Moreover, transgenic mice with an LC ablation may provide a more congruent model for human Alzheimer disease than transgenic mice with intact LC.