Artículo
Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease
Autor/es | Sánchez Mico, María
Jiménez Muñoz, Sebastián Gómez Arboledas, Ángela Muñoz Castro, Clara Romero Molina, Carmen Navarro Garrido, Victoria Vizuete Chacón, María Luisa Vitorica Ferrández, Francisco Javier |
Departamento | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular |
Fecha de publicación | 2020 |
Fecha de depósito | 2022-06-13 |
Publicado en |
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Resumen | 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, ... 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. |
Agencias financiadoras | Centro de Invesitgacion Biomedica en Red Enfermedades Neurodegenetativas. (CIBERNED) España Instituto de Salud Carlos III European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Junta de Andalucía Universidad de Málaga Universidad de Sevilla Fundación La Marató-TV3, Cataluña |
Identificador del proyecto | CB06/05/0094
CB06/05/1116 PI18/01556 PI18/01557 PY18-RT-2233 UMA18-FEDERJA-211 US-1262734 TV3 20141430 TV3 20141431 TV3 20141432 |
Cita | Sánchez Mico, M., Jiménez Muñoz, S., Gómez Arboledas, Á., Muñoz Castro, ., Romero Molina, C., Navarro Garrido, V.,...,Vitorica Ferrández, F.J. (2020). Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease. Glia, 69 (4), 997-1011. |
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