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.
Annals of Neurology
|October 24, 2017
Summary
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.
