Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease

Autor: Samuel J. Barnes, Larissa Stead, Emily Palmer, Bibiana C. Mota, Nicola Davis, Laura Lombardero, Rafael Rodríguez-Puertas, Magdalena Sastre, Vincenzo De Paola
Přispěvatelé: UK DRI Ltd
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Dendritic spine
lcsh:RC346-429
Mice
Neural Pathways
Neprilysin
biology
Microglia
Chemistry
General Neuroscience
amyloid-beta
Cell biology
medicine.anatomical_structure
Neurology
1107 Immunology
Encephalitis
Cytokines
Life Sciences & Biomedicine
Genetically modified mouse
Amyloid
Amyloid beta
Dendritic Spines
L-AAA
Immunology
organotypic cultures
Mice
Transgenic

Cellular and Molecular Neuroscience
Alzheimer Disease
medicine
Animals
Humans
Amyloid-β
Neuroinflammation
lcsh:Neurology. Diseases of the nervous system
Cell Size
Amyloid beta-Peptides
Science & Technology
Neurology & Neurosurgery
Interleukin-6
Research
synapsis
Neurosciences
astrocytes
1103 Clinical Sciences
Synapsis
Peptide Fragments
cytokines
Astrocytes
Synaptic plasticity
Synapses
biology.protein
Neurosciences & Neurology
1109 Neurosciences
2-Aminoadipic Acid
Zdroj: Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-12 (2021)
Addi: Archivo Digital para la Docencia y la Investigación
Universidad del País Vasco
Addi. Archivo Digital para la Docencia y la Investigación
instname
Universidad de Cantabria (UC)
Journal of Neuroinflammation
ISSN: 1742-2094
Popis: Background Astrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear. Methods To explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h. Results Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control. Conclusions Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.
Databáze: OpenAIRE