Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes

R. P. Gorter, J. Stephenson, E. Nutma, J. Anink, J. C. de Jonge, W. Baron, M. -C. Jahreiss, J. A. M. Belien, J. M. van Noort, C. Mijnsbergen, E. Aronica, S. Amor*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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AIMS: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterised by progressive loss of motor neurons, muscle weakness, spasticity, paralysis and death usually within 2-5 years of onset. Neuroinflammation is a hallmark of ALS pathology characterized by activation of glial cells, which respond by upregulating small heat shock proteins (HSPBs), but the exact underlying pathological mechanisms are still largely unknown. Here, we investigated the association between ALS disease duration, lower motor neuron loss, TDP-43 pathology, neuroinflammation and HSPB expression.

METHODS: With immunohistochemistry, we examined HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 expression in cervical, thoracic and sacral spinal cord regions in 12 ALS cases, 7 with short disease duration (SDD), 5 with moderate disease duration (MDD), and 10 age-matched controls. Expression was quantified using ImageJ to examine HSP expression, motor neuron numbers, microglial and astrocyte density and pTDP-43+ inclusions.

RESULTS: SDD was associated with elevated HSPB5 and 8 expression in lateral tract astrocytes, while HSP16.2 expression was increased in astrocytes in MDD cases. SDD cases had higher numbers of motor neurons and microglial activation than MDD cases, but similar levels of motor neurons with pTDP-43+ inclusions.

CONCLUSIONS: Increased expression of several HSPBs in lateral column astrocytes suggests that astrocytes play a role in the pathogenesis of ALS. SDD is associated with increased microgliosis, HSPB5 and 8 expression in astrocytes, and only minor changes in motor neuron loss. This suggests that the interaction between motor neurons, microglia and astrocytes determines neuronal fate and functional decline in ALS. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)459-475
Number of pages17
JournalNeuropathology and Applied Neurobiology
Issue number5
Early online date2018
Publication statusPublished - Aug-2019


  • amyotrophic lateral sclerosis
  • astrocytes
  • HSPB
  • inflammation
  • small heat shock proteins
  • TDP-43 pathology

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