gms | German Medical Science

Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

22.09.-24.09.2016, Hamburg

Astrocytes-restricted NF-kB activation enhances microglial response and induces a transient neuroprotection on Motor Neurons during ALS disease progression

Meeting Abstract

  • presenting/speaker Najwa Ouali Alami - University of Ulm, Neurology, Ulm, Germany; University of Ulm, International Graduate School in Molecular Medicine-University of Ulm, Ulm, Germany
  • Christine Schurr - University of Ulm, Institute of Physiological Chemistry, Ulm, Germany; University of Ulm, International Graduate School in Molecular Medicine-University of Ulm, Ulm, Germany
  • Tobias Boeckers - University of Ulm, Institute of Anatomy and Cell Biology, Ulm, Germany
  • Thomas Wirth - University of Ulm, Institute of Physiological Chemistry, Ulm, Germany
  • Albert Ludolph - University of Ulm, Neurology, Ulm, Germany
  • Bernd Baumann - University of Ulm, Institute of Physiological Chemistry, Ulm, Germany
  • Francesco Roselli - University of Ulm, Neurology, Ulm, Germany; University of Ulm, Institute of Anatomy and Cell Biology, Ulm, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. Scandinavian Neuropathological Society. Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS). Hamburg, 22.-24.09.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. Doc16dgnnNI5

doi: 10.3205/16dgnn12, urn:nbn:de:0183-16dgnn123

Veröffentlicht: 14. September 2016

© 2016 Ouali Alami et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to upper and lower Motor Neurons loss.

SOD1 G93A transgenic mice recapitulate the human disease and have revealed non-cell-autonomous mechanisms involved in MNs degeneration. However, the role of astrocytes and microglia in different phases of ALS progression is still unclear: there is no consensus whether and when astrocytes-driven inflammation may be protective or detrimental.

We used a genetic strategy based on key transcriptional regulator of inflammation NF-kB to drive astrocytic inflammatory response at different time points during disease progression.

We generated a triple transgenic mouse in which astrocyte-specific NF-kB activation is achieved by doxycycline-inducible expression of a constitutively active allele of IKK2 in the SOD1 G93A mouse model; the activation of NF-kB was restricted to astrocytes using a GFAP-mini-promoter-driven tTA gene.

Compared to mSOD1 littermates, the GFAP.tTA/tetO.IKK2-Ca/mSOD1 G93A triple transgenic mice (IKK2 induced from P20) displayed a prolonged onset phase but a reduced progression phase, leading to an unchanged lifespan, despite significant but biphasic effects on motor performance during the disease course.

In the early stages, when beneficial effects on motor performance are detected, we observed a significant decrease in MN disease markers (such as misfolded SOD1 burden, LC3A and p62 buildup) in correspondence of a massive rise in microglial density, amoeboid morphology and of a CD45+ microglial subpopulation appearance together with a significant CD4+ cells infiltration.

However, at P70 in the triple-tg mouse microglia assumed a CD68+ phenotype with a senescent morphology, whereas MN markers levels were equal to the mSOD1 mice, suggesting a loss of the beneficial effect driven by astrocytic IKK2/NF-kB activation.

Taken together our data demonstrated a bi-phasic role of inflammation in ALS pathogenic cascade, where astrocyte-orchestrated amplification of the inflammatory response is beneficial at early stages, but it turns to detrimental at later time points.

The elucidation of the mediators involved (which may include Wnt and IL-13) may offer new entry points for translational therapeutic interventions.