In a groundbreaking study published in Nature Metabolism this year, researchers have unveiled a previously unrecognized metabolic flexibility of neurons involving the interaction between sortilin, a sorting receptor, and apolipoprotein E3 (apoE3). This discovery reveals that neurons can harness long-chain fatty acids as an alternative source of metabolic fuel, a capability that challenges long-standing paradigms of brain energetics centered predominantly on glucose metabolism. The implications of this finding extend into understanding neuronal maintenance, neurodegenerative diseases, and metabolic regulation within the central nervous system.
For decades, glucose has been considered the primary energy substrate for neurons, fueling their high metabolic demands through oxidative phosphorylation. However, emerging evidence now indicates that neurons can metabolically adapt under certain circumstances, tapping into alternative substrates. This latest research specifically identifies how the interaction between sortilin and apoE3, a genetic variant famously associated with Alzheimer’s disease risk modulation, orchestrates the uptake and utilization of long-chain fatty acids in neurons. Such metabolic adaptation opens new avenues for exploring neuronal resilience and vulnerabilities in diverse physiological and pathological contexts.
Sortilin is a multi-faceted sorting receptor that mediates protein trafficking and lipid metabolism within cells. Its expression is particularly notable in the brain, where it regulates processes critical to neuronal function and survival. Apolipoprotein E (apoE), with its three most common isoforms E2, E3, and E4, has been heavily studied for its role in lipid transport and Alzheimer’s disease etiology. Notably, apoE3 is the most prevalent isoform and has generally been considered neuroprotective relative to apoE4. This study elucidates a direct biochemical and functional interaction between sortilin and apoE3 that enables neurons to extend their metabolic repertoire by utilizing long-chain fatty acids.
Using advanced biochemical assays, lipidomics, and neuronal culture models, the investigators demonstrated that apoE3-containing lipoprotein particles are recognized and internalized via sortilin on neuronal membranes. This receptor-ligand interaction facilitates the efficient uptake of fatty acids into neurons. Once internalized, these fatty acids undergo β-oxidation in mitochondria, contributing to ATP production and overall cellular energetics. Intriguingly, this mechanism appears to be isoform-specific, as apoE4, which is implicated in neurodegeneration, fails to support fatty acid uptake effectively, highlighting a potential metabolic disadvantage conferred by this allele.
The researchers further illustrated that under conditions where glucose availability is limited or metabolic stress is present, neurons upregulate sortilin expression to enhance fatty acid uptake. This adaptive response underscores a survival mechanism whereby neurons maintain energy homeostasis through substrate flexibility. Such metabolic plasticity might be crucial during periods of high energetic demand or in pathological states where glucose metabolism is impaired, such as in ischemia or Alzheimer’s disease.
Neuronal reliance on fatty acids as an energy source is surprising, given the dogma that neurons are inefficient at fatty acid oxidation and prone to lipotoxicity. However, the study presents compelling evidence that the sortilin-apoE3 axis finely tunes the delivery and catabolism of these lipids to avoid detrimental accumulation. This refined control suggests that neurons possess intrinsic mechanisms to safely exploit fatty acids, which could be vital for maintaining synaptic function, cellular repair, and redox balance.
The study’s methodology incorporated in vivo models complemented by in vitro systems to validate physiological relevance. Transgenic mice expressing human apoE3 and sortilin knock-out lines revealed diminished neuronal fatty acid uptake and compromised cognitive performance under metabolic stress. This phenotype reinforces the notion that the sortilin-apoE3 interaction is not only biochemically significant but also functionally critical for maintaining brain health and cognitive function.
On a molecular level, the binding affinity between sortilin and apoE3 was characterized using surface plasmon resonance and co-immunoprecipitation, showing a highly specific and robust interaction. This specificity may be a determinant of isoform-dependent effects, potentially explaining why apoE4’s altered structure lowers its binding efficiency to sortilin, subsequently impairing fatty acid utilization and possibly contributing to neurodegenerative pathology.
One of the most captivating implications of this research lies in its potential to redefine therapeutic strategies aimed at neurodegenerative diseases. By enhancing sortilin-mediated fatty acid uptake or mimicking the apoE3 interaction in apoE4 carriers, it may be possible to restore metabolic flexibility in vulnerable neurons, thereby mitigating energy deficits that underlie synaptic dysfunction and neuronal loss. Pharmacological or gene therapy approaches targeting this pathway could represent a novel class of metabolic neuroprotectants.
Moreover, this discovery resonates with the growing recognition that brain metabolism is intricately interconnected with systemic lipid homeostasis and that peripheral lipid metabolism disorders could influence central nervous system health. The sortilin-apoE3 interaction thus bridges lipoprotein biology and neuronal metabolism, suggesting that strategies to modulate systemic lipid profiles might have direct neuro-metabolic consequences.
The study also invites revisiting old theories about metabolic substrates in neuronal physiology. It illuminates the nuanced balance where neurons can prioritize glucose metabolism but retain the capacity to switch to fatty acids, ensuring energy supply continuity. This finding fuels broader inquiries about how neurons integrate various nutrient signals, interact with glial cells for lipid trafficking, and dynamically respond to metabolic cues during development, aging, and disease.
Furthermore, the research underscores the importance of considering genetic differences, such as apoE isoforms, when examining brain energetics. Individual genetic makeup may dictate metabolic flexibility or vulnerability, influencing disease risk and progression. Personalized medicine approaches could leverage such mechanistic insights to tailor interventions in neurodegenerative diseases and metabolic brain disorders.
This advancement builds on a foundation of emerging data that challenges the central dogma of exclusive glucose metabolism in neurons, expanding the dialogue to lipid metabolism and receptor-mediated nutrient uptake. It speaks to a more complex metabolic landscape where substrate availability, receptor expression, and genetic variability converge to dictate neuronal function and survival.
In conclusion, the elucidation of the sortilin-apoE3 interaction as a gateway for long-chain fatty acid utilization in neurons marks a paradigm shift in our understanding of brain metabolism. This finding not only enriches fundamental neuroscience but also opens promising translational avenues for mitigating neurodegeneration through metabolic modulation. As research continues, it will be fascinating to explore how this pathway interacts with other metabolic circuits and shapes brain health across the lifespan.
The intricate dance of molecules unveiled in this study reminds us that the brain’s metabolic terrain is multifaceted and finely regulated. Unlocking nature’s strategies for energy utilization offers a beacon of hope in the relentless quest to combat neurological diseases. By transforming our grasp of neuronal metabolism, this discovery stands poised to inspire innovative therapies and deepen our appreciation of the brain’s remarkable adaptability.
Subject of Research: Neuronal metabolism and lipid utilization mediated by sortilin and apolipoprotein E3 interaction
Article Title: Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel
Article References:
Greda, A.K., Gomes, J.P., Schmidt-Krueger, V. et al. Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01389-5
Image Credits: AI Generated
