Microglial dysfunction as a key pathological change in adrenomyeloneuropathy
Open accessAbstract
Objective: Mutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear. Methods: We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very‐long‐chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia. Results: Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis‐related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1‐deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8‐blocking antibody reduces phagocytic activity. Interpretation: Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813–827
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When microglia fail to degrade VLCFA-enriched myelin fragments and undergo apoptosis, their contents may be released into surrounding tissue and trigger an inflammatory reaction.
“When microglia fail to degrade VLCFA-enriched myelin fragments and undergo apoptosis, their contents may be released into surrounding tissue and trigger an inflammatory reaction [178].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [178]
The Results (page unavailable) report increased microglial phagocytosis and neuronal injury in AMN, explicitly in the absence of overt inflammation. The Discussion (page unavailable) describes microglial apoptosis only in connection with excess free VLCFA, not failure to degrade VLCFA-enriched myelin fragments. The paper does not describe apoptotic microglia releasing contents that trigger inflammation; its reported mechanism points in the opposite direction. (LLM, conf=0.82)
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Experimental — accuracy not yet measuredCultured microglia from Abcd1−/− mice appeared to be primed, reacting much more strongly to lipopolysaccharide challenge.
“However, cultured microglia appeared to be primed, as they reacted much more strongly to lipopolysaccharide (LPS) challenge [178].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [178]
Microglia may play a role in AMN in light of their pattern of increased activation and phagocytosis markers without pro-inflammatory signs in postmortem spinal cords of AMN patients.
“Microglia may play a role in light of their pattern of increased activation and phagocytosis markers without pro-inflammatory signs in postmortem spinal cords of AMN patients [178].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [178]
Similar results were seen in a mouse model of adrenomyeloneuropathy.
“Interestingly, similar results were obtained in a mouse model of adrenomyeloneuropathy.”
From Microglia in neurodegeneration (2018) · cites this paper as [142]
Oxidative stress and cellular components, especially microglial functions, seem to play a major role in the pathogenesis of X-ALD.
“Oxidative stress and cellular components, especially microglial functions, seem to play a major role in the pathogenesis of X-ALD [ 89 , 90 , 91 ].”
From Peroxisomal ABC Transporters: An Update (2021) · cites this paper as [91]
Microglia activation in Abcd1 knock-out mice seems to occur early, probably from eight months of age.
“However, microglia activation seems to occur early, probably from eight months of age [ 91 ]”
From Peroxisomal ABC Transporters: An Update (2021) · cites this paper as [91]
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References 47 · Cited by 54
- Authors
- Gong, Y., Sasidharan, N., Laheji, F., Frosch, M., Musolino, P., Tanzi, R., Kim, D. Y., Biffi, A., El Khoury, J., & Eichler, F.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Department of Neurology Massachusetts General Hospital, Harvard Medical School Boston MA
- Corresponding author
- Eichler, Florian
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2017-11
- Volume
- 82
- Issue
- 5
- Pages
- 813-827
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC5725816
- OpenAlex
- W2766111164
- Cited by
- 54
- References
- 47
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 8
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- University of Pennsylvania
- NIH (R01 NINDS)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- adrenomyeloneuropathy, microglial dysfunction, ABCD1 mutations, adrenoleukodystrophy, lysophosphatidylcholine, MFG-E8, TREM2, very long chain fatty acids, synaptic loss, axonal degeneration, spinal cord, neuroinflammation
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Animals, Antibodies, Antigens, Surface, Cells, Cultured, Humans, Lysophosphatidylcholines, Membrane Glycoproteins, Milk Proteins, Neurons, Phagocytosis, Receptors, Immunologic, Spinal Cord, Gene Expression, Case-Control Studies, Microglia, Mice, Knockout, Coculture Techniques, Primary Cell Culture
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