Plasmalogen deficiency in early Alzheimer's disease subjects and in animalmodels: molecular characterization using electrospray ionization mass spectrometry

To explore the hypothesis that alterations in ethanolamine plasmalogen may be directly related to the severity of dementia in Alzheimer's disease (AD) , we performed a systematic examination of plasmalogen content in cellular membranes of gray and white matter from different regions of human subjects with a spectrum of AD clinical dementia ratings (CDR) using electrospray i onization mass spectrometry (ESI/MS). The results demonstrate: (1) a dramat ic decrease in plasmalogen content (up to 40 mol% of total plasmalogen) in white matter at a very early stage of AD (i.e. CDR 0.5); (2) a correlation of the deficiency in gray matter plasmalogen content with the AD CDR (i.e. similar to 10 mol% of deficiency at CDR 0.5 (very mild dementia) to similar to 30 mol% of deficiency at CDR 3 (severe dementia); (3) an absence of alt erations of plasmalogen content and molecular species in cerebellar gray ma tter at any CDR despite dramatic alterations of plasmalogen content in cere bellar white matter. Alterations of ethanolamine plasmalogen content in two mouse models of AD, App(V717F) and APPsw, were also examined by ESI/MS. A plasmalogen deficiency was present (up to 10 mol% of total plasmalogen at t he age of 18 months) in cerebral cortices, but was absent in cerebella from both animal models. These results suggest plasmalogen deficiency may play an important role in the AD pathogenesis, particularly in the white matter, and suggest that altered plasmalogen content may contribute to neurodegene ration, synapse loss and synaptic dysfunction in AD.