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

Article type: Research Article

Authors: Pinçon, Anthony^{a; b} | Thomas, Mélanie H.^{a; b} | Huguet, Marion^{a; b} | Allouche, Ahmad^{a; b; e} | Colin, Julie C.^{a; b} | Georges, Alain^c | Derrien, Annabelle^{a; b} | Lanhers, Marie-Claire^{a; b} | Malaplate-Armand, Catherine^{a; b; d} | Oster, Thierry^{a; b} | Corbier, Catherine^{a; b} | Pillot, Thierry^{e; 1} | Olivier, Jean Luc^{a; b; d} | Yen, Frances T.^{a; b; e; *}

Affiliations: [a] Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace | [b] INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France | [c] Université de Lorraine, LARSA, IUT-NB, Vandoeuvre-lès-Nancy, France | [d] Biochemistry Department, CHU de Nancy, Nancy, France | [e] INSERM, Vandœuvre-lès-Nancy, France

Correspondence: [*] Correspondence to: Frances T. Yen, Université de Lorraine, ENSAIA, URAFPA, 2 avenue de la Forêt de Haye, TSA 40602, F-54518 Vandœuvre-lès-Nancy, France. Tel.: +33 3 83 59 61 84; Fax: +33 3 83 59 61 81; E-mail: [email protected].

Note: [1] Current address: SynAging SAS, Vandœuvre-lès-Nancy, France

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-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.

Keywords: Alzheimer's disease, amyloid-β oligomers, animal model, cholesterol, cognitive impairment, learning, lipolysis stimulated lipoprotein receptor, memory

DOI: 10.3233/JAD-142127

Journal: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 195-204, 2015