Metabolomic Identification in Cerebrospinal Fluid of the Effects of High Dietary Cholesterol in a Rabbit Model of Alzheimer's Disease.
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disorder, manifesting clinical symptoms of cognitive impairment and dementia. The vast majority of cases are late onset AD (LOAD), which are genetically heterogeneous and occur sporadically. The neuropathological changes of LOAD can be reproduced by supplementing a rabbit's diet with 2% cholesterol for 12 weeks.


METHODS
In the present study, a non-targeted Fourier transform ion cyclotron resonance mass spectrometry based metabolomics approach and multivariate statistics were used to survey the effect of cholesterol on cerebrospinal fluid metabolites over a 12 week time-course.


RESULTS
Of the 6515 accurate masses detected in the rabbit CSF, 375 showed significant differences in intensity (p < 0.05) between samples collected at different time points. Further analysis of top 95 (p < 0.01) revealed four clusters of metabolites with different expression patterns throughout the course of the cholesterol treatment. The majority of effects were observed in 12 weeks of cholesterol treated samples, while certain masses showed transient changes at 8 weeks but returned back to near the levels of the controls at 12 weeks. The masses that started to change 8 weeks into the treatment may represent early metabolic changes linked to certain defects in the brain related to AD development. Putative metabolite identifications revealed certain phosphorylated glycerolipids and peptide fragments decreased after 8 weeks of cholesterol treatment.


CONCLUSIONS
This study showed that there are specific metabolic perturbations which occur in the CSF as a result of high cholesterol loading. Given the changes of short peptide fragments in particular, the effects are likely the consequence of brain degeneration caused by high cholesterol levels. Further investigations of these masses will lead to a greater understanding of the metabolic mechanisms associated with cholesterol-related AD development. Some of these masses may be used as candidates for the development of diagnostic, prognostic or theranostic markers.
Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada ; Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Qing Yan
QY
Liu
Phenomenome Discoveries Inc. Saskatoon, SK, Canada S7N 4L8.
Erin J
EJ
Bingham
Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada.
Susan M
SM
Twine
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota.
Jonathan D
JD
Geiger
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota.
Othman
O
Ghribi
Alzheimer’s disease; Cerebrospinal Fluid; Cholesterol; Metabolomics; Rabbit Model