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

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-β peptide₄₂ (Aβ₄₂), 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 Aβ₄₂-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric Aβ₄₂ 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 Aβ₄₂-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 Aβ₄₂-injected LSR^+/− mice as compared to Aβ₄₂-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 a risk factor for AD.