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Increased Susceptibility of Dyslipidemic LSR+/- Mice to Amyloid Stress is Associated with Changes in Cortical Cholesterol Levels

Abstract : Alzheimer's disease (AD) is a neurodegenerative disease that has been linked to changes in cholesterol metabolism. Neuronal cholesterol content significantly influences the pro-apoptotic effect of amyloid-beta peptide(42) (A beta(42)), which plays a key role in AD development. We previously reported that aged mice with reduced expression of the lipolysis stimulated lipoprotein receptor (LSR+/-), demonstrate membrane cholesterol accumulation and decreased intracellular lipid droplets in several brain regions, suggesting a potential role of LSR in brain cholesterol distribution. We questioned if these changes rendered the LSR+/- mouse more susceptible to A beta(42)-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric A beta(42) in male 15-month old LSR+/+ and LSR+/- mice led to impairment in learning and long-term memory and decreased cortical cholesterol content of both groups; these effects were significantly amplified in the A beta(42)-injected LSR+/- group. Total latency of the Morris test was significantly and negatively correlated with cortical cholesterol content of the LSR+/- mice, but not of controls. Significantly lower cortical PSD95 and SNAP-25 levels were detected in A beta(42)-injected LSR+/- mice as compared to A beta(42)-injected LSR+/+ mice. In addition, 24S-hydroxy cholesterol metabolite levels were significantly higher in the cortex of LSR+/- mice. Taken together, these results suggest that changes in cortex cholesterol regulation as a result of the LSR+/- genotype were linked to increased susceptibility to amyloid stress, and we would therefore propose the aged LSR+/- mouse as a new model for understanding the link between modified cholesterol regulation as risk factor for AD.
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Submitted on : Monday, August 21, 2017 - 4:34:48 PM
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Anthony Pincon, Melanie H. Thomas, Marion Huguet, Ahmad Allouche, Julie C. Colin, et al.. Increased Susceptibility of Dyslipidemic LSR+/- Mice to Amyloid Stress is Associated with Changes in Cortical Cholesterol Levels. Journal of Alzheimer's Disease, 2015, 45 (1), pp.195-204. ⟨10.3233/JAD-142127⟩. ⟨hal-01575780⟩



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