Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function

The sterol sensor SCAP is a key regulator of SREBP-2, the major transcription factor controlling cholesterol synthesis. Recently, we showed that there is a global down-regulation of cholesterol synthetic genes, as well as SREBP-2, in the brains of diabetic mice, leading to a reduction of cholesterol...

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Bibliographic Details
Published in:PLoS biology 2013-04, Vol.11 (4), p.e1001532
Main Authors: Suzuki, Ryo, Ferris, Heather A, Chee, Melissa J, Maratos-Flier, Eleftheria, Kahn, C Ronald
Format: Article
Language:English
Subjects:
Animals
Biology
Brain - physiopathology
Cholesterol
Cholesterol - biosynthesis
Cognition
Diabetes
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - physiopathology
Excitatory Postsynaptic Potentials
Garlic
Gene Deletion
Haploinsufficiency
Hippocampus - physiopathology
Injections, Intraventricular
Insulin - administration & dosage
Intracellular Signaling Peptides and Proteins - deficiency
Intracellular Signaling Peptides and Proteins - genetics
Male
Membrane Proteins - deficiency
Membrane Proteins - genetics
Mice
Mice, Inbred C57BL
Proteins
Receptors, G-Protein-Coupled - metabolism
Recognition, Psychology
Rodents
Synapses - metabolism
Synaptic Transmission
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Summary:The sterol sensor SCAP is a key regulator of SREBP-2, the major transcription factor controlling cholesterol synthesis. Recently, we showed that there is a global down-regulation of cholesterol synthetic genes, as well as SREBP-2, in the brains of diabetic mice, leading to a reduction of cholesterol synthesis. We now show that in mouse models of type 1 and type 2 diabetes, this is, in part, the result of a decrease of SCAP. Homozygous disruption of the Scap gene in the brains of mice causes perinatal lethality associated with microcephaly and gliosis. Mice with haploinsufficiency of Scap in the brain show a 60% reduction of SCAP protein and ~30% reduction in brain cholesterol synthesis, similar to what is observed in diabetic mice. This results in impaired synaptic transmission, as measured by decreased paired pulse facilitation and long-term potentiation, and is associated with behavioral and cognitive changes. Thus, reduction of SCAP and the consequent suppression of cholesterol synthesis in the brain may play an important role in the increased rates of cognitive decline and Alzheimer disease observed in diabetic states.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.1001532