A novel inducible animal model for studying chronic plasmalogen deficiency associated with Alzheimer's disease.

Plasmalogens are vinyl-ether glycerophospholipids critical for the structure and function of neuronal membranes. Deficient plasmalogen levels are associated with neurodegenerative diseases, particularly Alzheimer's disease (AD), which has led to the hypothesis that plasmalogen deficiency might drive disease onset and progression. However, the lack of a suitable animal model with late-onset plasmalogen deficiency has prevented testing of this hypothesis. The goal of this project was therefore to develop and characterize a mouse model capable of undergoing a plasmalogen deficiency only in adulthood, mirroring the chronic decline thought to occur in AD. We report here the creation of a novel animal model containing a tamoxifen-inducible knockout of the Gnpat gene encoding the first step in the plasmalogen biosynthetic pathway. Tamoxifen treatment in adult animals resulted in a significant reduction of plasmalogens in both the circulation and tissues as early as four weeks. By four months, changes in behavior and nerve function were observed, with strong correlations between residual brain plasmalogen levels, hyperactivity, and latency. The model will be useful for further elucidating the role of plasmalogens in AD and evaluating plasmalogen therapies.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tara Smith reports financial support was provided by Med-Life Discoveries LP. Kaeli J Knudsen reports financial support was provided by Med-Life Discoveries LP. Shawn A Ritchie reports financial support was provided by Med-Life Discoveries LP. Tara Smith reports a relationship with Med-Life Discoveries LP that includes: employment. Kaeli J Knudsen reports a relationship with Med-Life Discoveries LP that includes: employment. Shawn A Ritchie reports a relationship with Med-Life Discoveries LP that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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