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Ablation of astrocytes affects Aβ degradation, microglia activation and synaptic connectivity in an ex vivo model of Alzheimer’s disease
Author(s) -
Davis Nicola,
Mota Bibiana Castagna,
Stead Larissa,
Palmer Emily OC,
Lombardero Laura,
RodriguezPuertas Rafael,
de Paola Vincenzo,
Barnes Samuel J,
Sastre Magdalena
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047419
Subject(s) - microglia , neuroinflammation , proinflammatory cytokine , ex vivo , astrocyte , neuroglia , amyloid (mycology) , genetically modified mouse , hippocampal formation , neurodegeneration , neprilysin , dendritic spine , microbiology and biotechnology , transgene , pathology , biology , chemistry , in vivo , neuroscience , medicine , immunology , inflammation , central nervous system , biochemistry , disease , gene , enzyme
Background Astrocytes provide 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 through which they affect neuroinflammation, amyloid pathology and synaptic density in AD remain unclear. Method To explore the role of astrocytes on amyloid pathology and neuroinflammatory markers, we pharmacologically ablated astrocytes in organotypic brain culture slices (OBCSs) generated from the 5XFAD mouse model of amyloidosis with selective astrocytic toxin L‐alphaaminoadipate (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 amyloid‐beta (Aβ)42, or double transgenics Thy‐1‐GFP/5XFAD mice treated with L‐AAA or vehicle for 24h. Result Treatment of OBCSs with L‐AAA resulted in an increased expression of proinflammatory cytokines, such as TNF‐α in conditioned media, without changes in microglial density. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, associated with reduced expression of Neprilysin and Apolipoprotein E, which are involved in Aβ clearance. In addition, 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 the Aβ degrading enzyme 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 analysed. 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. Conclusion Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.