MDA 2025: Cholesterol receptor ‘critical’ in sporadic ALS disease
LDLR may be key driver of neurotoxicity, per new research in mouse model
Signaling at the low-density lipoprotein receptor, known as LDLR, may be an important driver of neurodegeneration in sporadic amyotrophic lateral sclerosis (ALS), according to new preclinical research by U.S. scientists.
In earlier work, the scientists discovered that mice injected with cerebrospinal fluid, or CSF — the fluid that surrounds the brain and spinal cord — from sporadic ALS patients developed classic signs of the disease, and that the cholesterol transporter protein apolipoprotein B-100, called ApoB for short, seemed to be driving this effect.
Now, the team has found that ApoB exerts its neurotoxic effects in these mice by binding to LDLR, which normally helps regulate cholesterol levels in the blood.
The new findings were discussed in an oral presentation at the Muscular Dystrophy Association’s 2025 MDA Clinical & Scientific Conference, held last week in Dallas and virtually.
“The LDL receptor is critical for mediating ApoB-induced neurotoxicity,” Jamie Wong, PhD, a researcher at Tisch Multiple Sclerosis Research Center of New York, said in the presentation, titled “Low-density lipoprotein receptor is critical for sporadic ALS CSF-induced neurotoxicity.”
Scientists used mouse model they developed of sporadic ALS
ALS is a neurodegenerative disease in which motor neurons — the nerve cells involved in muscle control — progressively degenerate. The resulting muscle weakness drives symptoms including movement problems and difficulties with swallowing, speaking, and breathing.
About 10% of ALS cases are familial, meaning more than one person in a family is affected by the disease. This likely is due to the inheritance of disease-related genetic mutations. The remaining majority of cases, however, are sporadic, where there’s no known family history of ALS.
The underlying cause of sporadic ALS is believed to involve complex interactions between genetic and environmental factors.
Wong noted that although it’s the more predominant form, sporadic ALS remains “relatively understudied.” The scientist attributed this in part to the fact that it’s harder to develop animal models for this disease type.
A few years ago, the research team did in fact develop a mouse model of sporadic ALS, made by injecting CSF from sporadic ALS patients into the spinal canal of healthy mice.
The mice quickly developed hallmark signs of ALS, such as motor impairments, motor neuron, or nerve cell, loss, and the abnormal accumulation of the TDP-43 protein in the wrong place within cells. These disease-related changes were not observed when mice were injected with CSF from familial ALS patients.
As such, according to the researchers, ApoB seemed to be an underlying driver of the observed neurotoxicity. When it was depleted from patient CSF, the bodily fluid was no longer neurotoxic in mice or in human-derived motor neurons. Moreover, administering just ApoB with no other CSF components, was “able to recapitulate all of the neurotoxic effects that [were] observed with sporadic ALS CSF,” Wong said.
The scientist explained that ApoB normally resides in the blood, but not in the CSF. Previous work has associated elevated blood levels of ApoB with a higher risk of developing ALS.
Blocking LDLR seen to prevent neurotoxic effects in mice
In the body, ApoB binds to two different receptor proteins — LDLR and sortilin — both of which have been previously linked to nerve cell death. In their experiments, the scientists set out to investigate if either of these receptors mediate the neurotoxic effects of ApoB.
The team found that mice injected with sporadic ALS CSF or ApoB alone exhibited increased levels of both LDLR and sortilin in the spinal cord. This did not occur, however, in mice given ApoB-depleted CSF.
In the human-derived motor neurons, ApoB treatment similarly increased levels of the two receptor proteins and was associated with a reduced size of motor neuron clusters. Importantly, per the team, this effect of ApoB on motor neuron clusters was still observed when sortilin was blocked.
“This suggests that the ApoB-induced neurotoxicity is not mediated by sortilin,” Wong said.
Blocking LDLR prevented the neurotoxic effects of ApoB on motor neuron clusters. Moreover, mice genetically engineered to lack LDLR were not sensitive to the neurotoxic effects of sporadic ALS CSF or ApoB — they did not develop significant motor disability, motor neuron loss, or TDP-43 abnormalities as normal mice had.
“So this suggests that Apob-induced neurotoxicity is mediated through the LDL receptor,” Wong noted.
[These findings] suggest that ApoB binding to LDLR is a critical step for inducing motor neuron degeneration in [sporadic] ALS.
The scientist said that the team is now doing a pilot study to look at gene activity changes in the spinal cords of the mouse model.
“Hopefully this will give us some further insight into the mechanisms downstream of LDLR and ApoB which are contributing to motor neuron degeneration in sporadic ALS,” Wong said.
Overall, according to the researchers, the findings presented at the MDA conference “suggest that ApoB binding to LDLR is a critical step for inducing motor neuron degeneration in sALS.” The team added that “future studies … [into] motor neuron death” will be aimed at providing elucidation.
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