Excessive lipid droplets in brain cells, particularly microglia, are characteristic of a number of neurodegenerative conditions. Even though cholesterol is vital to cell function, excess cholesterol in cells is toxic, changing behavior for the worse or even killing cells given a large enough excess. A range of other evidence is also supportive of a role for changes in lipid metabolism, including cholesterol metabolism, in the development of conditions such as Alzheimer's disease. Here, researchers report a new finding that implicates the cholesterol intake of neurons in an area of the brain known to be vulnerable to Alzheimer's pathology.
Researchers gathered a large collection of brain tissue samples from deceased patients and compared two different brain regions within the same individual. From each brain, they collected a sample of the dopamine-producing Substantia Nigra (SN), a region resistant to degeneration in AD, and the noradrenaline-producing Locus Coeruleus (LC), a region that is highly vulnerable to Alzheimer's disease. The researchers then analyzed RNA from the different brain regions to measure the expression levels of different genes. They used this gene expression data to provide a full picture of which cellular processes vary between these two neuronal populations.
Their results showed a striking segregation between the LC and SN in how they regulate cholesterol levels. "One key difference between the brain regions had to do with cholesterol metabolism and homeostasis. The LC neurons exhibit signatures suggesting that they are super cholesterol-hungry - these neurons are doing both their best to produce their own cholesterol and take in as much as possible. The SN, on the other hand, doesn't have the same level of demands."
Using immunohistochemistry tissue staining - the gold standard to demonstrate proteins at single cell level in tissue from different cases - the researchers validated these findings. They found that the LC neurons express higher levels of LDLR, a part of a receptor called sigma-2 that helps cells take in cholesterol molecules. A consequence of this, is that toxic amyloid-beta oligomers (small clumps of amyloid-beta protein) may "sneak in" to the neurons via this same receptor. Conversely, the SN expresses a selective degrader of LDLR, making it less susceptible to these oligomers.
Link: https://www.eurekalert.org/news-releases/1078311
View the full article at FightAging
