The brain is a special organ, and immune cells there called microglia work to repair damage and maintain the health of neural networks. About ten percent of brain cells are estimated to be microglia, and they move through the brain, looking for debris and harmful proteins. Once microglia identify insults, the cells engulf and remove them. But in the aging brain, this cleanup crew can lag behind; harmful proteins build up and damage goes unrepaired. Now scientists are exploring the role these aged microglia play in Alzheimer’s disease.
Small variations in the sequences of genes can have a range of impacts on biology, some of which may raise (or lower) the risk of certain diseases. Variations in a gene called PICALM have been associated with an increased risk of late-onset Alzheimer’s.
Reporting in Nature, researchers have now determined that PICALM can have a massive influence on microglia. Variations in this gene can disrupt microglia function, and raise the risk of Alzheimer’s, explained study co-author Ari Sudwarts, PhD, a postdoctoral research scholar at the University of South Florida.
PICALM is now the third-most significant gene for late-onset Alzheimer’s disease risk, noted the researchers. While changes in these risk genes do not necessarily cause a carrier to get Alzheimer’s, they can raise that carrier’s risk. Other things can also influence that risk, such as habits and lifestyle choices.
This study assessed the impact of PICALM variants on microglia’s ability to clear debris. One variant reduced that function, which can cause cholesterol and lipids to accumulate. “Understanding the functions disrupted by a specific risk gene gives new targets for developing pharmaceuticals for patients who have this genetic variant,” said Sudwarts.
Further work showed that one variant of PICALM, known as the minor allele, is carried by an estimated 30% of people, and seems to protect carriers against Alzheimer’s. But another variant, called the major allele, does not.
The team investigated these variants in microglia. The minor PICALM (risk) allele was only found in microglia. The major allele was shown to lower the levels of PICALM protein in microglia. These reduced PICALM protein levels impair organelles called lysosomes in microglia, which affects how microglia can clean up lipids, and molecules like amyloids in the brain.
“This creates these compact structures called lipid droplets that cause further havoc in a cell, and it impedes the microglia from doing its job,” said co-corresponding study author Gopal Thinakaran, PhD, of the USF Health Byrd Alzheimer’s Center, among other appointments. “It’s extremely rare to have a story develop like this, and it took five years to unfold.”
This study has shown how lipid dysrergulaiton and microglia can contribute to Alzheimer’s development. “The knowledge we have gained adds one more piece to the Alzheimer’s puzzle we are putting together,” added Thinakaran.
Sources: University of South Florida, Nature