A defect in a crucial gene, SORL 1, that helps deliver proteins and cholesterol in brain cells could generate plaque, leading to the onset of Alzheimer’s, says a new study published in Cell on 22 August.
The researchers from the Brigham Research Institute at Brigham and Women’s Hospital (BWH), UK, found how two proteins that drive the early onset of Alzheimer’s were influenced by the gene SORL 1.The study results could pave the way for developing new treatment approaches for the debilitating neurological condition.
“Rare mutations have been found in the SORL1 gene in several families with early-onset Alzheimer’s,” said Dr Tracy Young-Pearse, the corresponding author of the study and an associate professor at the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital.
In Alzheimer’s, more common variants in the SORL1 gene have been associated with increased risk for Alzheimer’s disease in genetic studies involving tens of thousands of people, she added.
SORL 1 gene makes a protein whose function is to facilitate the delivery of proteins and fats inside cells. This particular protein also helps neurons connect better, aiding synaptic plasticity (forming new synaptic connections).
Earlier studies showed that SORL 1gene plays a role in keeping away the amyloid precursor protein (APP) from interacting with APOE and tau protein. As a result, it prevents plaque formation in nerve cells. However, mutations in SORL 1 have been associated with increased production of amyloid beta plaques, contributing to the progression of Alzheimer’s.
Connections of the gene in Alzheimer’s
In this study, researchers wanted to find what would happen to different brain cells if the SORL 1 gene was absent. For their experiments, they used induced pluripotent stem cells (iPSCs). iPSCs are reprogrammed body cells that behave like stem cells and can regenerate any other type of cell. In this study, the team used body cells donated by people with Alzheimer’s and converted them to iPSCs.
“iPSCs capture human genetic variation that animal models cannot capture,” says Dr Young-Pearse. She further explains, “Each person has different genetic risk and resilience factors for Alzheimer’s disease, and iPSC technology allows researchers to capture those factors in an experimental system.”
The researchers knocked off the SORL1 gene from the Alzheimer’s derived iPSCs using CRISPR technologies. This led to the absence of the SORL 1 gene in subsequent generations of cells. They observed that when the SORL1 gene was absent, it reduced two crucial proteins in the neurons — APOE and CLU.
The APOE protein is responsible for delivering and prevent aggregation of fats like cholesterol in brain cells. At the same time, CLU regulates cell survival and death, inflammation and stress response. Mutations in the genes that make APOE and CLU are known genetic risk factors for Alzheimer’s, along with SORL 1.
Hence, the team deduced that the SORL1 gene could impact APOE and CLU levels, thereby governing the health of neurons.
In Alzheimer’s, the fat composition in neurons was disrupted, indicating that the absence of SORL1 contributes to Alzheimer’s. As the level of APOE protein is influenced by SORL 1, researchers also speculate this can protect the neurons.
Implications of the study
“Alzheimer’s disease varies in terms of its age of onset, rate of progression and molecular pathways that cause the disease,” says Dr Young-Pearse. This study contributes to understanding different types of Alzheimer’s disease and identifies potential therapeutic targets for people with genetic risk factors involving SORL1, she adds.
We are still in the process of understanding various neurological conditions like Alzheimer’s. Similar studies will help explore different mechanisms and genes’ involvement in Alzheimer’s, which could help develop effective personalised treatments.
