Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids

Tada, Mari; Konno, Tetsuo; Tada, Masayoshi; Tezuka, Toshiki; Miura, Takeshi; Mezaki, Naomi; Okazaki, Kenichi; Arakawa, Masato; Itoh, Kyoko; Yamamoto, Toru; Yokoo, Hideaki; Yagi, Nobuaki; Ishihara, Kenji; Horie, Minoru; Takebayashi, Hirohide; Toyoshima, Yasuko; Naito, Makoto; Onodera, Osamu; Nishizawa, Masatoyo; Takahashi, Hitoshi; Ikeuchi, Takeshi; Kakita, Akiyoshi

doi:10.1002/ana.24754

Cited by 59 publications

(68 citation statements)

References 29 publications

(42 reference statements)

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“…The molecular mechanism could involve suppression of mitophagy either directly (Ulland et al, 2017;Wang et al, 2019) or as an indirect consequence of overloading of the degradative pathway by the ingested myelin (Safaiyan et al, 2016). Furthermore, as observed in the mouse model ( Figure 5C), overexpression of TREM2 also occurs in the white matter of ALSP patients ( Figure 6E), where others have documented the presence of lipid-laden macrophages (Tada et al, 2016;Lin et al, 2010). Thus, decreased autophagy may contribute to ALSP pathology, and the benefits of stimulation of autophagy should be further explored.…”

Section: Discussionmentioning

confidence: 76%

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling

et al. 2020

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Section: Discussionmentioning

confidence: 76%

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling

et al. 2020

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“…Of interest, both MSA [65][66][67] and HDLS [68] share pathological astro-and microgliosis. In a previous study we found that MSA patients had lower protein levels of G-CSF, a growth factor belonging to the same family as CSF, in the prefrontal cortex of MSA brains [20].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

Rydbirk

Folke

Busato

et al. 2020

acta neuropathol commun

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Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P < 0.05), of which one probe mapping to the AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14 + CD16 ++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

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“…In this sense, deficiencies on key genes for the microglial survival and/or proliferation (such as CSF1R or TREM2) are associated with rare hereditary neurodegenerative diseases, such as adult-onset leukoencephalopathy with axonal spheroids or Nasu-Hakola disease (respectively) (Paloneva et al, 2000 , 2002 ; Chitu et al, 2016 ). In both diseases, the microglial response and, more relevant, the microglial survival seems to be compromised (Nataf et al, 2005 ; Satoh et al, 2011 ; Konno et al, 2014 ; Tada et al, 2016 ). On the other hand, missense mutations in TREM2 (such as R47H TREM2) produce an increases risk for late-onset AD (Guerreiro et al, 2013 ; Korvatska et al, 2015 ; Yeh et al, 2016 ) and a reduction in the number of microglial cells surrounding Aβ plaques in models.…”

Section: Soluble Phospho-tau Is Responsible For the Microglial Degenementioning

confidence: 99%

Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative

Navarro

Sánchez-Mejías

Jiménez

et al. 2018

Front. Aging Neurosci.

179

135

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Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer’s disease (AD), the role of microglia is far to be elucidated. In this “mini-review” article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around amyloid-beta (Aβ) plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simply reflect the lower and probably slower Aβ production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V–VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown.

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Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids

Abstract: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations. Ann Neurol 2016;80:554-565.

Cited by 59 publications

References 29 publications

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative

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