A research team headed by investigators at Brigham and Women’s Hospital reported on the results of a study in which they used stem cells from Alzheimer’s disease (AD) patients to identify a potential mechanism by which a gene known as SORL1 may impact the risk for the neurodegenerative disorder. Their work found that loss of normal SORL1 function leads to a reduction in two key proteins, APOE and CLU, which are known to be involved in AD, and which play an essential role in the neurons of healthy individuals. The study findings suggest a potential new strategy for AD treatment, especially for patients not responsive to existing therapies. 

“Understanding the subtypes of AD is relatively new in the field of neurology research,” said Tracy Young-Pearse, PhD, of the Ann Romney Center for Neurological Diseases. “This is getting at a precision neurology approach, with which we can better predict which patients may be responsive to Alzheimer’s treatment strategies that attack specific genes or target the problems they cause.” Young-Pearse is corresponding author of the team’s published paper in Cell Reports, which is titled, “Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1,” in which they concluded, “Taken together, we demonstrate that AD-relevant SORL1 loss of function results in neuron-specific reduction in APOE and CLU and dysregulated lipid homeostasis.”

AD varies widely in its age of onset, presentation, and severity. Key neurological features of AD, including the accumulation of amyloid-beta (Aβ) plaques in the brain, also vary across individuals. The anti-amyloid therapies, aducanumab and lecanemab, have received FDA accelerated and traditional approval, respectively, but not all patients respond to these drugs, warranting other treatment options.

Historically, researchers have studied the genes APP, PSEN1, and PSEN2, as potent genetic drivers of AD. These genes are commonly mutated in hereditary, early-onset AD (EOAD), in which disease is diagnosed before 65 years of age. Preclinical models and cell-based systems largely rely on mutations in these genes to model AD, even though in many people with late-onset (sporadic) AD, a more complex interaction between genes, lifestyle, and environment determines the presentation of AD. 

Recently, the SORL1 gene has received increased attention since variations in this gene have been associated with both early- and late-onset AD. However, little is known about how damage to SORL1 leads to disease. “SORL1 belongs to both the vacuolar protein sorting 10 containing receptor family and the low-density lipoprotein (LDL) receptor family,” the authors wrote. “Single-nucleotide polymorphisms (SNPs) at the SORL1 locus are associated with AD in genome-wide association studies (GWASs).” Importantly, they continued, several SORL1 coding variants have been identified in a subset of patients with EOAD, while reduced expression of SORL1 has been reported in the cerebrospinal fluid (CSF) and postmortem brains of individuals with late-onset AD. “Together, these data suggest that SORL1 plays a causal role in AD.”

For their new study, the researchers utilized a stem-cell-based approach that examined natural genetic variability in AD patients to gain insight into an alternative pathway driving disease. They used CRISPR technologies to remove the SORL1 gene from progenitor stem cells derived from participants in two Alzheimer’s research cohorts, the Religious Order Studies and Rush Memory and Aging Project. The investigators then programmed these SORL-1 null stem cells to differentiate into four different kinds of brain cells, and examined the impact of removing SORL1 on each cell type. “… we performed transcriptomic profiling comparing wild-type (WT) to SORL1-null iPSC lines that were differentiated to a variety of brain cell types (neurons, astrocytes, microglia, endothelial/epithelial cells),” they explained. The most dramatic impact was seen in neurons and in the brain’s astrocyte support cells. Neurons lacking SORL1 demonstrated an especially prominent reduction in the levels of two key AD proteins, APOE and CLU. “Most intriguing to us was the finding that SORL1 plays a neuron-specific role in the regulation of APOE and CLU levels,” they stated. “This finding is of particular interest given that APOE and CLU variants also are high-confidence genetic risk factors for AD, in addition to SORL1.” Interestingly, loss of SORL1 in neurons led to an increase in Aβ levels and phosphorylation of tau.

The researchers verified their lab-based results by examining natural genetic variation in SORL1 expression in the brain tissue of 50 members of the cohorts, finding again that lower SORL1 activity in neurons was correlated with reduced APOE and CLU in these people. “We further interrogated the relationship between APOE, CLU, and SORL1 in a set of 50 iPSC lines derived from the Religious Order Studies and Memory and Aging Project (ROSMAP) aging cohorts,” they stated. “Intriguingly, following differentiation, natural variation in SORL1 levels was strongly associated with both APOE and CLU protein levels in neurons but not in astrocytes.”

Further, single-nucleus RNA sequencing (snRNA-seq) analyses of brain tissue revealed a significant association of SORL1 with both APOE and CLU expression in neurons, “supporting the relevance of this relationship in the aged human brain,” the investigators stated. Without APOE and CLU, neurons cannot properly regulate lipids, which accumulate in droplets that may impair neurons’ abilities to communicate with each other. 

“Taken together, we demonstrate that AD-relevant SORL1 loss of function results in neuron-specific reduction in APOE and CLU and dysregulated lipid homeostasis,” the team commented. “Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. These studies provide a mechanistic link between strong genetic risk factors for AD.”

The researchers are continuing to study other pathways that may lead to AD, such as those involving microglia, which are brain cells that perform immune functions. By using study models and techniques reflective of AD presentation in the general population, the researchers hope to identify additional biological pathways important in AD.

“Our study is one of the first with human cells from a large collection of individuals to try to understand the ‘molecular road’ that starts with SORL1, which we now see converges with APOE,” said Young-Pearse, commenting on the newly reported findings. “Our research points to the importance of developing interventions that target these and other molecular roads to Alzheimer’s disease. The more we can understand subtype-specific differences in AD, the better we will be able to design rational therapeutic interventions to try to fix the problem that is primarily driving disease in each patient.”

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