Scientists at Sanford Burnham Prebys announced on July 17 that a protein called SORLA may help protect the brain from toxic tau tangles associated with Alzheimer's disease and other neurodegenerative disorders. The findings, published in Science Advances, suggest that enhancing this protein's activity could lead to new treatments for diseases known as tauopathies.
Tau proteins typically stabilize neuronal microtubule filaments throughout the nervous system. However, in conditions such as Alzheimer's disease, these proteins can clump together inside nerve cells to form tau tangles, which are linked to cognitive impairment and nerve cell death.
The study focused on sorting-related receptor with A-type repeats (SORLA) and its role in safeguarding against harmful effects of tau accumulation. Researchers crossbred mice engineered to produce extra human SORLA protein with mice prone to developing tau tangles, brain atrophy, and cognitive deficits. This allowed them to observe how increased SORLA levels affected tau buildup and related neurological damage.
Results showed that an overabundance of SORLA protected against several processes associated with neurodegeneration. These included reducing hyperphosphorylation of tau—a process where too many phosphate groups attach to the protein—and preventing misshapen tau from attracting more proteins to form clumps. Enhanced SORLA also preserved synaptic plasticity and maintained connections between neurons.
"When you upregulate SORLA, you can suppress the negative effects found in tauopathies," said Huijie Huang, PhD, a staff scientist at Sanford Burnham Prebys and lead author of the study. "We found there was less brain atrophy and less tau accumulation, which was very exciting to see."
Researchers also examined mice lacking the gene for SORLA (Sorl1), finding worsened outcomes compared to those with extra SORLA. The team used sequencing techniques to analyze changes in gene expression and spatial relationships within brain tissue under different levels of SORLA activity.
Further findings indicated that upregulated SORLA prevented detrimental changes in synapses while suppressing disease-related gene expression patterns in glial cells—brain cells that support neurons. "One particularly notable finding that we can build on is the upregulation of a member of the plexin-B family of receptors in the absence of SORLA," said Huijie Huang.
Tim Huang added, "There are unique drugs that can target this class of receptors that we may be able to apply to tau-related dementia disorders... One potential future direction is to repurpose these drugs." Ongoing research will include grafting human neurons or glial cells into mouse brains for further study.
"Because we're looking at human disease, it's more informative if we can observe the modulation and dysfunction of SORLA in the context of a human cell inside a diseased brain environment," said Tim Huang.
