P3-006: mining the neural and plasma phospholipidome to identify critical lipid determinants of alzheimer's disease conversion

Commonly conceptualized as undulating fields of identical molecules, neuronal membranes are, in fact, made up of hundreds of chemically and molecularly diverse lipid species. Here, we asked whether impairment of phosphocholine (PC) membrane can be used to predict transition from a pre-symptomatic to symptomatic state in (1) an experimental mouse model of familial Alzheimer's Disease (AD) and (2) in a clinical pilot study of mild cognitive impairment (MCI) and sporadic AD. The PC lipidome was profiled in hippocampus, temporal cortex, plasma at 2, 4, 6, and 8 months in the TgCRND8 AD mouse model and their NonTg littermates following assessment of learning and memory impairment in the Morris Water Maze. These results were compared to clinical circulating profiles of a pilot cohort of 21 cognitively normal, 17 mild cognitive impairment (MCI) patients, and 32 AD patients. Patients were assessed using the Clinical Dementia Rating (CDR), Structured Clinical Interview for DSM-IV Disorders - Depression scale (SCID-I), Hamilton Rating Scale for Depression [HAM-D], and Mini Mental State Examination (MMSE). PCs were isolated using a modified Bligh & Dyer method adapted for efficient extraction of phosphatidylcholines, alkyacylphosphocholines, plasmenylacylphosphocholines, and acylformylglycerophosphocholines. Profiling was performed by LC-ESI-MS with in both precursor ion mode (discovery) and multiple reaction monitoring mode (quantitation). 499 unique PC lipid species were identified. In NonTg mice, PCs clearly clustered into expected patterns of “stable” critical compositions, structural species being actively mobilized to maintain these critical compositions, and bioactive signaling molecules. The abundance of 24 PC species was significantly altered in 5.5 month old TgCRND8 mice. Significant correlations between the abundance of 13 species in either the hippocampus or temporal cortex were detected that could be predicted by associated changes in the circulating lipidome. Experimental profiles were then compared to clinical profiles as part of a pilot study. Increases in 3 critical species correlated with CDR and/or MMSE scores in MCI and AD and 4 species correlated with HAM-D scores in controls. These data provide proof of principle justifying a larger clinical investigation into the capacity of the circulating phospholipidome to predict disease progression.