Abstract
Author SummaryDiabetes 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.
Highlights
The brain is the most cholesterol rich organ in the body, containing more than 20% of the sterol pool and almost all of the cholesterol is produced in situ [1]
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
Summary
The brain is the most cholesterol rich organ in the body, containing more than 20% of the sterol pool and almost all of the cholesterol is produced in situ [1]. Multiple in vitro studies have indicated that cholesterol in the brain is important for synapse biogenesis and vesicle formation [2,3]. Cholesterol synthesis is a highly regulated process controlled by the master transcriptional regulator SREBP-2. SREBP-2 is transcribed and translated into an inactive precursor that is sequestered in the endoplasmic reticulum (ER). When sterol levels are low, the sterol sensor SCAP is able to chaperone SREBP-2 to the Golgi apparatus where it is cleaved to release a transcriptionally active form that can enter the nucleus [4]. In times of sterol abundance, SCAP is bound by sterols and remains sequestered in the ER along with the unprocessed SREBP-2 [4]
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