RT Journal Article
T1 Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease.
A1 Sanchez-Mico, Maria V
A1 Jimenez, Sebastian
A1 Gomez-Arboledas, Angela
A1 Muñoz-Castro, Clara
A1 Romero-Molina, Carmen
A1 Navarro, Victoria
A1 Sanchez-Mejias, Elisabeth
A1 Nuñez-Diaz, Cristina
A1 Sanchez-Varo, Raquel
A1 Galea, Elena
A1 Davila, Jose C
A1 Vizuete, Marisa
A1 Gutierrez, Antonia
A1 Vitorica, Javier
K1 Alzheimer
K1 amyloid-beta
K1 astrocytes
K1 dystrophic synapses
K1 microglia
K1 pathology
K1 phagocytosis
AB Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid-β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid-β peptides), Tau (containing AT8- and AT100-positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs-APP, but not AT8/AT100-positive SNs-Tau, as compared with SNs-WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12-month-old APP mice, since only 1.60 ± 3.81% of peri-plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia-mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia-dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid-β alone. Taken together, our data suggest that amyloid-β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid-β, as well as of peri-plaque dystrophic synapses containing amyloid-β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.
PB John Wiley & Sons, Inc.
YR 2021
FD 2021-02-06
LK http://hdl.handle.net/10668/16745
UL http://hdl.handle.net/10668/16745
LA en
NO Sanchez-Mico MV, Jimenez S, Gomez-Arboledas A, Muñoz-Castro C, Romero-Molina C, Navarro V, et al. Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease. Glia. 2021 Apr;69(4):997-1011.
DS RISalud
RD Apr 6, 2025