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RP2E INRA Université de Lorraine

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

J Alzheimers Dis, 45 (1), pp. 195-204.

Pincon, A., Thomas, M., Huguet, M., Allouche, A., Colin, J., Georges, A., Derrien, A., Lanhers, M.-C., Malaplate-Armand, C., Oster, T., Corbier, C., Pillot, T., Olivier, J.-L., Yen, F.T.

2015

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 peptide42 (Abeta42), 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 Abeta42-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric Abeta42 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 Abeta42- 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 Abeta42-injected LSR+/− mice as compared to Abeta42-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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