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Symposium

Can we identify common pathways mediated by Glial Cells in neurodegeneration?

03/10 – 10:30
Aula Magna – Entresuelo PABELLÓN 2 (Main Lecture Hall – Mezzanine, Building 2)

Chair:
Juana Pasquini (Short CV)
[IQUIFIB] Instituto de Química y Fisicoquímica Biologicas “Prof. Alejandro Paladini”

The Simposium try to demonstrate the interrelationship between the different glia cells in the central nervous system (CNS) We also included tha Schwann cells

SPEAKERS

Carla Caruso:
INBIOMED UBA-CONICET. Facultad de Medicina, UBA.
Title:The role of astrocytes in Huntington’s disease.

Astrocytes are fundamental glial cells that play a crucial role in maintaining brain
homeostasis. In recent decades, our understanding of astrocyte functions has advanced
significantly. Neurodegenerative diseases are characterized by the selective loss of
neurons, increased glial activation, and glial dysfunction. Growing evidence indicates
considerable regional heterogeneity among astrocytes in terms of morphology, gene
expression, and function. Huntington’s disease (HD) is a neurodegenerative disorder
that initially affects the striatum and later the cortex, leading to motor, cognitive, and
psychiatric impairments. Given the pivotal role of astrocytes, there is increasing interest
in their potential as therapeutic targets in neurodegenerative conditions. Our research
highlights functional differences between astrocytes in the striatum and those in the
cortex. Using a mouse model of HD, we investigated regional astrocyte differences and
explored their potential therapeutic relevance.

Maria Claudia Gonzalez Deniselle:
Lab. de Bioquímica Neuroendócrina.  Instituto de Biología y Medicina Experimental   IByME-CONICET.
Title: Myelin as a target of steroid hormones in motoneuron degeneration.  

Amyotrophic lateral sclerosis (ALS) is a progressive motoneuron disease associated
with demyelination and neuroinflammation. The incidence of ALS is greater in men;
however, it increases in women after menopause, suggesting a role for sex steroids in
the disease. Low testosterone concentrations have been detected in the cerebrospinal
fluid of ALS patients and in the central nervous system of male Wobbler mice, a well-
characterized spontaneous model of motoneuron degeneration. Wobblers exhibit
motoneuron degeneration, astro- and microgliosis, and myelin disruption within the
cervical spinal cord. Testosterone is a complex steroid that exerts its effects directly via
androgen receptors (AR) and indirectly via estrogen receptors (ER) after aromatization
into estradiol. In this study, we investigated whether male Wobblers receiving a 2-
month testosterone treatment, with or without the aromatase inhibitor anastrozole,
exhibited modulation of myelin-associated features and neuroinflammation. Myelin
characteristics were assessed via Luxol fast blue (LFB) staining, semithin sections,
transmission electron microscopy (TEM), and immunolabeling for myelin basic protein
(MBP) and proteolipid protein (PLP). Inflammatory responses were analyzed by
quantifying IBA1+ microglia, and the mRNA expression of CD11b, TLR4, TNFαR1, and
P2Y12R. Glutamatergic homeostasis was evaluated through glutamine synthetase and
GLT-1. Testosterone-treated Wobblers showed enhanced LFB, MBP, and PLP staining.
A marked increase in the thickness of the myelin sheaths proportional to the axon
diameter was shown in the white matter of testosterone-treated Wobblers (Y = 0.2313
*x +0.1756; p <0.001) and controls (Y = 0.1094 * x +0.3906; p <0.001). However, the
thickness of the myelin sheaths was independent of the axon diameter in steroid-free
and testosterone plus anastrozole-treated Wobbler mice. and myelin compaction was
better compared to Wobblers and testosterone plus anastrozole-treated Wobblers,
which exhibited disruption of myelin lamellae. Wobbler mice showed a marked increase
in IBA1+ microglia and elevated expression of inflammatory genes, which were
significantly attenuated by testosterone administration, but not by the combined
testosterone and anastrozole treatment. Furthermore, glutamine synthetase-positive
cells and GLT-1 immunoreactivity were preserved in testosterone-treated Wobblers but
reduced in both Wobblers and testosterone plus anastrozole-treated Wobblers.
Functionally, testosterone improved muscle mass, grip strength, and limb morphology,
whereas these benefits were absent following testosterone and anastrozole treatment.
These findings indicate that testosterone confers protective effects on myelin and
modulates neuroinflammatory and glutamatergic pathways in Wobbler mice, supporting
its translational potential in motoneuron disorders.

Pablo Iribarren:
Profesor Titular e Investigador Principal CIBICI-CONICET Facultad de Ciencias Químicas  Universidad Nacional de Cordoba. Córdoba Argentina.
Title: Microglial Cells: foes or friends during neurodegeneration?

Inflammation represents a complex biological response to tissue damage, pathogens, and irritants. Macrophages migrate to injured tissues in response to inflammation-
induced chemoattractants, playing critical roles in both the promotion and regulation of inflammatory processes. Our previous work demonstrated that TLR2 selectively activates autophagic flux in microglial cells. Stimulation of microglial cells with alpha-synuclein or LPS triggers the production of pro-inflammatory cytokines and nitric oxide (NO), leading to microglia-mediated neuronal cell death in vitro. Notably, the activation of autophagy in microglial cells attenuates the production of pro-inflammatory cytokines, NO, and associated neurotoxicity

On the other hand, preliminary results from our laboratory suggest that alpha-synuclein, which is a potential ligand of TLR2, may induce autophagy in macrophages, and this response would depend on the activation of TBK-1 and OPTN.

Our findings highlight that autophagy activation in microglial cells can assume diverse roles across multiple layers of microglial responses, with its effects shaped by
contextual factors.

In addition, evaluation of the activated microglial cells transcriptome may provide clues about the complex pathways modulated by TLR2.

Transcriptomic analysis of microglial cells suggests that TLR2 stimulation modulates several pro-inflammatory.

Felipe Court
Full Professor, Center for Integrative Biology, Universidad Mayor, Chile. Director, FONDAP Geroscience Center for Brain Health and Metabolism
Title:Schwann Cell-Axon interactions in Homeostasis, Degeneration and Axonal Regeneration.

Peripheral nerve integrity depends on dynamic interactions between axons and Schwann cells (SCs). While axonal degeneration has long been considered a neuron-intrinsic process, our recent work reveals that SCs actively initiate axonal disintegration via a cytokinesis-like mechanism that triggers mitochondrial-dependent fragmentation. This glia-driven process reframes our understanding of degeneration, particularly in aging and disease.

Regeneration, conversely, relies on SC reprogramming into a repair phenotype that promotes axon growth and immune modulation. In aging and chronic denervation, we find this program is impaired not just by failed reprogramming, but by the accumulation of senescent SCs, a newly identified phenotype that inhibits regeneration and fuels inflammation. Removing these cells restores regenerative capacity. These findings position Schwann cells as key regulators of both axon loss and repair, and as promising therapeutic targets for improving nerve regeneration in aging and disease.

Symposium Conclusions:
Jorge Correale
Instituto de Química y Fisicoquímica Biológica (IQUIFIB) Facultad de y Farmacia y Bioquímica  Universidad de Buenos Aires CONICET y Departamento de Neurología FLENI. Buenos Aires  Argentina