Is microglial apoptosis an early pathogenic change in cerebral X‐linked adrenoleukodystrophy?

Eichler, Florian; Ren, Jia Qian; Cossoy, Michael; Rietsch, Anna; Nagpal, Sameer; Moser, Ann B.; Frosch, Matthew P.; Ransohoff, Richard M.

doi:10.1002/ana.21391

Cited by 151 publications

(158 citation statements)

References 31 publications

(32 reference statements)

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“…For some time, it has been known that excess VLCFA (40 µM and above) affects membrane function and causes toxicity to adrenocortical cells, oligodendrocytes, astrocytes, and neurons 43, 44. For example, excess free VLCFA induces depolarization of mitochondria and deregulation of the intracellular calcium homeostasis,42 and in the brain, this can cause activation and apoptosis of microglia 4. However, more relevant than these supraphysiological doses are the lower doses that we used, which in isolation do not cause cell death.…”

Section: Discussionmentioning

confidence: 99%

“…The most severe form of X‐ALD, childhood cerebral ALD (CALD), manifests as acute demyelination in childhood with prominent lymphocytic infiltration and a distinct zone of microglial cell death surrounding the inflammatory lesion 3, 4. The more common phenotype is adrenomyeloneuropathy (AMN), an axonopathy of the spinal cord with notable absence of inflammatory lesions or lymphocytic infiltration, but numerous microglia and macrophages.…”

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confidence: 99%

“…High‐dose LPC injections lead to brain demyelination in mice, but the impact of LPC upon axonal degeneration and AMN pathogenesis has not been studied 4. Notably, levels of VLCFA in plasma do not correlate with phenotype or severity, and attempts at lowering VLCFA have so far shown no effect upon AMN progression.…”

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confidence: 99%

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Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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ObjectiveMutations 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.MethodsWe 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.ResultsWithin 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.InterpretationSpinal 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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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“…Additionally, in AD mouse models, bone marrow-derived macrophages have been shown to limit plaque growth (45) and genetically modified monocytes can modulate AD pathology (46). Importantly, microglial apoptosis has been implicated in X-linked adrenoleukodystrophy (ALD) (21), and beneficial clinical outcomes have been reported in ALD patients subject to therapies using nonmutant myeloid cells (47). Furthermore, replacement of dysfunctional microglia through wildtype bone marrow transplantation resulted in improved functional outcome in a mouse model of Rett syndrome (22).…”

Section: Discussionmentioning

confidence: 99%

“…However, resident microglia are lost or can become dysfunctional in certain CNS disorders and during aging (21)(22)(23)(24)(25). Thus, the competence of circulating monocytes to respond to microglial loss or complete dysfunction is unknown.…”

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Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

Varvel

Grathwohl

Baumann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Under most physiological circumstances, monocytes are excluded from parenchymal CNS tissues. When widespread monocyte entry occurs, their numbers decrease shortly after engraftment in the presence of microglia. However, some disease processes lead to focal and selective loss, or dysfunction, of microglia, and microglial senescence typifies the aged brain. In this regard, the long-term engraftment of monocytes in the microglia-depleted brain remains unknown. Here, we report a model in which a niche for myeloid cells was created through microglia depletion. We show that microglia-depleted brain regions of CD11b-HSVTK transgenic mice are repopulated with new Iba-1-positive cells within 2 wk. The engrafted cells expressed high levels of CD45 and CCR2 and appeared in a wave-like pattern frequently associated with blood vessels, suggesting the engrafted cells were peripheral monocytes. Although two times more numerous and morphologically distinct from resident microglia up to 27 wk after initial engraftment, the overall distribution of the engrafted cells was remarkably similar to that of microglia. Two-photon in vivo imaging revealed that the engrafted myeloid cells extended their processes toward an ATP source and displayed intracellular calcium transients. Moreover, the engrafted cells migrated toward areas of kainic acid-induced neuronal death. These data provide evidence that circulating monocytes have the potential to occupy the adult CNS myeloid niche normally inhabited by microglia and identify a strong homeostatic drive to maintain the myeloid component in the mature brain.chemokines | myeloid cell heterogeneity | neuroinflammation | in vivo calcium imaging

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Molecular Genetics of X‐linked Adrenoleukodystrophy

Kemp

2014

Encyclopedia of Life Sciences

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X‐linked adrenoleukodystrophy (X‐ALD), which affects 1 in 17 000 newborns, is one of the most puzzling inborn errors of metabolism of the central nervous system. All X‐ALD patients have mutations in the ABCD1 gene, which affect the function of the encoded protein ALDP, an adenosine triphosphate (ATP) ‐binding cassette transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta‐oxidation of very long‐chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in the accumulation of VLCFA in the plasma and tissues. The clinical spectrum ranges from progressive myelopathy in adults to fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). In the absence of a genotype–phenotype correlation, the disease course remains completely unpredictable, even within families, and is therefore defined by modifier genes, epigenetics and the environment. For the majority of patients there is no curative therapy. Key Concepts: The clinical spectrum of X‐ALD ranges from a progressive myelopathy (adrenomyeloneuropathy) in adult males and females to a fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). X‐ALD has been diagnosed in all geographic regions and ethnic groups, and there is no evidence that the prevalence varies with ethnic background. Mutations in the ABCD1 gene have no predictive value with respect to the clinical outcome of a patient. Approximately 65% of heterozygous females develop AMN by the age of 60 years. VLCFA accumulating in X‐ALD mostly result from endogenous synthesis through elongation of LCFA by ELOVL1, the VLCFA‐specific elongase. Newborn screening allows prospective monitoring and early intervention.

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Is microglial apoptosis an early pathogenic change in cerebral X‐linked adrenoleukodystrophy?

Cited by 151 publications

References 31 publications

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

Molecular Genetics of X‐linked Adrenoleukodystrophy

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