Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

Chenju Yi; Pascal Ezan; Paola Fernández; Julien Schmitt; Juan C Sáez; Christian Giaume; Annette Koulakoff

doi:10.1002/glia.23182

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

Glia. 2017 Oct;65(10):1607-1625. doi: 10.1002/glia.23182. Epub 2017 Jul 13.

Authors

Chenju Yi¹, Pascal Ezan¹, Paola Fernández^{2

3}, Julien Schmitt⁴, Juan C Sáez^{2

3}, Christian Giaume¹, Annette Koulakoff¹

Affiliations

¹ Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, PSL Research University, Paris, 75005, France.
² Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
³ Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
⁴ Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine, Institut de Biologie Paris Seine (NPS-IBPS), Cerebellum Navigation and Memory team (CeZaMe), Paris, 75005, France.

PMID: 28703353
DOI: 10.1002/glia.23182

Abstract

The contribution of reactive gliosis to the pathological phenotype of Alzheimer's disease (AD) opened the way for therapeutic strategies targeting glial cells instead of neurons. In such context, connexin hemichannels were proposed recently as potential targets since neuronal suffering is alleviated when connexin expression is genetically suppressed in astrocytes of a murine model of AD. Here, we show that boldine, an alkaloid from the boldo tree, inhibited hemichannel activity in astrocytes and microglia without affecting gap junctional communication in culture and acute hippocampal slices. Long-term oral administration of boldine in AD mice prevented the increase in glial hemichannel activity, astrocytic Ca²⁺ signal, ATP and glutamate release and alleviated hippocampal neuronal suffering. These findings highlight the important pathological role of hemichannels in AD mice. The neuroprotective effect of boldine treatment might provide the basis for future pharmacological strategies that target glial hemichannels to reduce neuronal damage in neurodegenerative diseases.

Keywords: Alzheimers'disease; astrocytes; connexin; hemichannel; microglia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / genetics
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Aporphines / pharmacology*
Aporphines / therapeutic use*
Cells, Cultured
Connexins / genetics
Connexins / metabolism*
Disease Models, Animal
Gap Junctions / drug effects
Gap Junctions / metabolism
Hippocampus / cytology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria / metabolism
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurites / metabolism
Neurites / pathology
Neuroglia / drug effects*
Neuroglia / metabolism
Neuromuscular Depolarizing Agents / pharmacology
Neuromuscular Depolarizing Agents / therapeutic use
Neurons / drug effects*
Neurons / physiology
Neurotransmitter Agents / metabolism
Presenilin-1 / genetics
Presenilin-1 / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Aporphines
Connexins
Nerve Tissue Proteins
Neuromuscular Depolarizing Agents
Neurotransmitter Agents
Panx1 protein, mouse
Presenilin-1
presenilin 1, mouse
boldine