91影库

Alzheimer’s disease, or AD, is the best-known neurodegenerative disorder affecting cognitive functioning and accounts for 60% to 80% of dementia cases. Understanding the progression of AD is relevant for its treatment, and multiple hypotheses exist to explain how the disease progresses.

One of these is the tau hypothesis; tau is a protein that stabilizes microtubules, an important component in neurons. Misfolding of tau leads to its aggregation in cells. This accumulation of tau starts spreading throughout the brain of AD patients by moving from cell to cell.

In a recent published in the Journal of Biological Chemistry, Joanna Cooper at the University of Maryland School of Medicine, Aurelien Lathuiliere at Massachusetts General Hospital and a team of researchers focused on a receptor called Sortilin-related receptor 1, or SORL1, that is involved in tau accumulation inside the cells.

“SORL1 has been associated with Alzheimer’s disease in a sense that mutations have been found that may be causative, but there is no consensus as to how that is working,” Cooper said. “Most research previously has focused on its role with amyloid beta, which is the other main player in Alzheimer’s disease.”

Prior research showed that lower levels of SORL1 increase the generation of a polypeptide called amyloid beta, the main component of amyloid plaque found in AD patients. This new research indicates SORL1 increases tau seeding, highlighting a contradiction in the role of SORL1 in AD progression.

“I think it’s a new line of research with the potential to have translational implications for patients,” Lathuiliere said.

With amyloid beta, loss of function of SORL1 is problematic, whereas in the context of tau there might also be a gain of toxic function, Cooper explained. “That adds a whole dichotomy into thinking about what SORL1 does,” she said.

Researchers need to do more work in the lab to determine if SORL1 is a therapeutically relevant target for AD patients.

“It was really easy to identify that it acts as a direct binding partner to tau,” Cooper said. That simple experiment quickly gave conclusive results.

 “It was a lot more challenging to dig into what can SORL1 do and try to understand something that gives us insight it’s actual physiological function.”

The team used surface plasmon resonance to detect the binding affinity of SORL1 with tau. They conducted immunofluorescence staining and F枚rster resonance energy transfer assays to understand where tau was positioned among cells and to understand the implication of specific SORL1 mutations in AD patients.

Even if SORL1 isn’t targeted directly for therapeutics, this finding “provides context for the machinery that is helping to traffic tau and opens up a lot more understanding about how that process happens,” Cooper said.

Overall, tau seeding causes AD to progress. Understanding where tau is within and among cells and the receptors responsible for cellular uptake and transport will help researchers explore avenues for treating AD.