A scientist has found a protein that may find a new way to treat Alzheimer’s, which came after tests revealed raising levels of SORLA in the brain found to decrease several types of disease-related damage. The finding, published online in Science Advances, seems to lead in the direction of bolstering SORLA’s actions against hostile tau modifications and maybe relieving some of the processes, which drive neurodegeneration. But has not been shown convincingly as a cure in humans yet.
SORLA (also known as sortilin-related receptor 1 and encoded by the gene SORL1) has previously been noted in recent Alzheimer’s research as variations in the SORL1 gene are connected to an increased risk of the disease. The protein appears to have a key role in intracellular sorting and trafficking of various molecules including proteins involved in Alzheimer’s relevant pathways.
Most recently, he centered his studies on tau, a protein that plays an important role in keeping the internal shape of nerve cells. Abnormal formations of plaques of the tau protein have been found to be numerous and hyperphosphorylated, an important factor involved in many neurological illnesses including Alzheimer’s disease.
In an established mouse model of tauopathy, Sanford Burnham Prebys researchers sought to examine the effects of overexpressing SORLA. Transgenic mice that expressed more SORLA had Really decreased amounts of tau hyperphosphorylation as well as diminished tau seeding and capacity to promote further pathogenic changes of tau (Pr01). They had Really decreased brain atrophy and diminished loss of communication between neurons.
Additional to the findings mentioned above the group also noted alterations in the supporting cells of the brain called glia. Elevated levels of SORLA seemed to have a suppressive effect on disease involvement in glia.
This is intriguing since a novel Alzheimer’s linkage pathway has been tied to SORLA. Preliminary research from 2026 indicated Really reduced SORLA expression levels in brain tissues obtained from Alzheimer’s patients. Interestingly, metabolic and cell function disorders were detected when SORLA was knocked down in human microglia and in cultured neurons.
A separate 2006 study confirmed the role of SORLA on amyloid-beta. It was shown in female Alzheimer’s mouse models that estradiol up-regulated SORLA thereby redirecting amyloid precursor protein toward cellular pathways that produced less amyloid-beta, and reduced the protein when levels were knocked-down.
All of these studies lead to the hypothesis that SORLA sits at an interesting crossroads of many processes involved in AD, including protein trafficking, amyloid processing, tau pathology, lipid metabolism, and cellular stress. This leaves the protein an intriguing potential therapeutic target rather than a mere marker of the disease.
It would also be interesting to look for drugs which could upregulate SORLA levels. Previous studies have suggested the existence of a PKC/ and -arrestin2 dependent pathway in cells that led to SORLA degradation. In vitro and mouse studies showed that inhibiting this pathway elevated SORLA levels and resulted in lower amyloidogenic processing and cognition scores.