Microglial dysfunction as a key pathological change in adrenomyeloneuropathy
Yi Gong1, Nikhil Sasidharan1, Fiza Laheji1
1Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
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.
Insights
Spinal cord microglia in adrenomyeloneuropathy (AMN) exhibit heightened phagocytosis due to ABCD1 mutations, leading to neuronal injury. Blocking this phagocytosis may offer a therapeutic strategy for AMN.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Adrenoleukodystrophy (ALD) is a neurodegenerative disease caused by ABCD1 mutations.
- Adrenomyeloneuropathy (AMN) is the most common manifestation in adult males, characterized by spinal cord axonopathy.
- The role of microglia in the spinal cord pathology of AMN is not well understood.
Purpose of the Study:
- To investigate the function of spinal cord microglia in AMN.
- To determine the impact of ABCD1 deficiency on microglial activity and neuronal integrity.
- To explore the role of very-long-chain fatty acids and lysophosphatidylcholine (LPC) in microglial dysfunction.
Main Methods:
- Assessment of spinal cord microglia in human and mouse models of AMN.
- In vitro studies of ABCD1-deficient microglia and neuronal phagocytosis.
- Examination of the effects of lysophosphatidylcholine (LPC C26:0) on microglial behavior.
- Use of MFGE8-blocking antibodies to inhibit phagocytosis.
Main Results:
- Upregulation of phagocytosis markers (MFGE8, TREM2) in spinal cord microglia of AMN patients and mice, preceding synapse loss and complement activation.
- Microglial activation occurred without overt inflammation.
- LPC C26:0 exacerbated phagocytosis and neuronal injury in ABCD1-deficient microglia.
- Inhibition of MFGE8 reduced microglial phagocytic activity.
Conclusions:
- Spinal cord microglia in AMN are primed for phagocytosis due to ABCD1 deficiency and an altered metabolic environment.
- Targeting microglial phagocytosis or specific receptors like MFGE8 may be a therapeutic approach to mitigate synapse loss and axonal degeneration in AMN.
