Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function.
Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function.
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DOI：
10.1371/journal.pbio.1001532
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Suzuki R;Ferris HA;Chee MJ;Maratos-Flier E;Kahn CR
A conditional knockout of SCAP in the mouse brain identifies impaired cholesterol synthesis as a potential link between diabetes and altered brain 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 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. Diabetes is associated with an increased risk of Alzheimer disease, depression, and cognitive decline, but the causal link underlying these associations is unclear. We previously showed that in diabetic mice there is a reduction in brain synthesis of cholesterol, which is required for normal formation of synapses between neurons. Here we show that this deficit is caused, in part, by a reduction in the levels of SCAP, a protein known to help regulate cholesterol synthesis by promoting the relocalization, cleavage, and liberation of the key transcription factor SREBP2. These changes in cholesterol biosynthesis are rescued by treatment of the diabetic mice with insulin. When the level of SCAP in the brains of non-diabetic mice is lowered by genetic manipulation, there is a decrease in cholesterol synthesis in the brain, and this results in impaired signaling between neurons, memory deficits, and abnormal responses to stress. These findings indicate that the reduction in SCAP associated with diabetes can contribute to changes in cognitive function in this disease.
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