Abstract
Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia–neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays an important role in brain cholesterol homeostasis. Aged heterozygote Lsr+/− mice show altered brain cholesterol distribution and increased susceptibility to amyloid stress. Since LSR expression is higher in astroglia as compared to neurons, we sought to determine if astroglial LSR deficiency could lead to cognitive defects similar to those of Alzheimer’s disease (AD). Cre recombinase was activated in adult Glast-CreERT/lsrfl/fl mice by tamoxifen to induce astroglial Lsr deletion. Behavioral phenotyping of young and old astroglial Lsr KO animals revealed hyperactivity during the nocturnal period, deficits in olfactory function affecting social memory and causing possible apathy, as well as visual memory and short-term working memory problems, and deficits similar to those reported in neurodegenerative diseases, such as AD. Furthermore, GFAP staining revealed astroglial activation in the olfactory bulb. Therefore, astroglial LSR is important for working, spatial, and social memory related to sensory input, and represents a novel pathway for the study of brain aging and neurodegeneration.
Highlights
Cholesterol transport and homeostasis are tightly regulated in the central nervous system (CNS) to ensure proper development and functioning of the brain throughout its lifetime
Astrocytes provide neurons with cholesterol in the form of lipoproteins, which are primarily apolipoprotein (Apo)E and ApoJ containing high-density lipoprotein-like (HDL-like) particles [9]. These HDL-like particles are exported from the astrocytes via ATP-binding cassette A1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1) transporters [10], where they bind to lipoprotein receptors via ApoE and are internalized into target cells through receptor-mediated transport processes
No significant differences in body mass were observed between the wild-type controls (WT) and cKO groups, nor was any mortality observed during the experimental period (Supplementary Figure S3)
Summary
Cholesterol transport and homeostasis are tightly regulated in the central nervous system (CNS) to ensure proper development and functioning of the brain throughout its lifetime. The LSR is a multimeric protein complex composed of three subunits (α, α’, β), which are activated in the presence of free fatty acids, thereby revealing a binding site that recognizes ApoB and ApoE [11] It was first discovered in the liver [12], and later its expression in the CNS was shown [13]. To decipher the role of astroglial LSR in the cholesterol crosstalk within the CNS, we used a conditional Cre/lox recombination system developed in a astroglia-specific transgenic mouse line that allows for temporally controlled site-specific recombination [19] This approach depends on cell-specific expression of tamoxifen (TAM)-dependent CreERT2 recombinase.
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