Alzheimer’s disease (AD) is the most common form of dementia affecting approximately 55 million people worldwide. In a new study published in Alzheimer’s and Dementia titled, “Familial Alzheimer’s disease mutation identifies novel role of SORLA in release of neurotrophic exosomes,” researchers from Aarhus University have identified a defect in the production of exosomes, vesicles that act as messengers to transfer proteins, lipids, and nucleic acids to other cells, associated with a mutation seen in dementia patients. The work was led by Kristian Juul-Madsen, PhD, assistant professor in the department of biomedicine at Aarhus University.
SORL1 is a gene that codes for the intracellular sorting receptor protein, Sortilin-related receptor with A-type repeats (SORLA), that is linked to the inherited form of Alzheimer’s and involved in influencing the processing and trafficking of amyloid precursor protein (APP) and tau protein. SORLA is highly expressed in neurons and microglia in the human brain and directs multiple target proteins between golgi, cell surface, and endo-lysosomal compartments to sort paths central to endocytic and secretory functions of cells. Mutations in SORLA failed to promote the release and neurotrophic qualities of exosomes, a defect attributed to altered exosomal content of microRNAs controlling neuronal maturation.
“[The results] tells us that exosomes produced particularly by the brain’s immune cells play an important role in maintaining brain health—and that mutations leading to fewer and poorer quality exosomes are associated with increased risk of Alzheimer’s,” said Juul-Madsen.
While numerous coding SORL1 variants have been identified in patients with AD, hundreds of coding gene variants in individuals with absent or uninformative short pedigrees have made it difficult to determine disease-causing from common receptor variants. Rather than focusing on genetic loss of known receptor actions, the authors used an unbiased screening approach to interrogate alterations in a mutant receptor interactome. Notably, the study focused on mutation N1358S identified in an individual with early onset AD.
The biogenesis of exosomes is a complex process tightly connected to vesicular trafficking in endocytic compartments. Cells with the SORLA mutation produced 30% fewer exosomes. Exosomes that were produced were significantly worse at stimulating the growth and maturation of surrounding cells and up to 50% less effective than in cells where the SORLA-protein is not mutated. Defects in exosome release were seen in both neurons and microglia lacking SORLA or expressing the N1358S variant, documenting a generalized role for the receptor in formation of exosomes in multiple cell types.
The authors suggest that reduced content of microRNAs and RNA-binding proteins in exosomes from mutant SORLA microglia may explain the diminished neurotrophic qualities. Additionally, while N1358S is a rare variant, the authors note that defects in microglia-neuron cross talk through exosomes with this mutation may possess broader significance for the receptor’s role in the control of aging brain health and AD.
Future directions for the treatments for AD can include stimulating the function of SORLA to produce improved exosomes or targeting other known receptors that can enhance exosome production.
