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Targeted suppression of lipoprotein receptor LSR in astrocytes leads to olfactory and memory deficits in mice

International Journal of Molecular Sciences, 23 (4), 2049.

El Hajj, A., Herzine, A., Calcagno, G., Desor, F., Djelti, F., Bombail, V., Denis, I., Oster, T., Malaplate, C., Vigier, M., Kaminski, S., Pauron, L., Corbier, C., Yen, F.T., Lanhers, M.-C., Claudepierre, T.

2022

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 i16nduce 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.

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