1. Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease
- Author
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Clara Muñoz-Castro, Carmen Romero-Molina, Elena Galea, Antonia Gutierrez, Raquel Sanchez-Varo, Javier Vitorica, Elisabeth Sanchez-Mejias, Angela Gomez-Arboledas, Maria V. Sanchez-Mico, Cristina Nuñez-Diaz, Sebastian Jimenez, Victoria Navarro, Jose Carlos Davila, Marisa Vizuete, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, 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, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), European Commission, and Fundació La Marató de TV3
- Subjects
0301 basic medicine ,Amyloid beta ,Phagocytosis ,Hippocampus ,microglia ,Amyloid‐beta ,Mice, Transgenic ,Plaque, Amyloid ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Amyloid beta-Protein Precursor ,Mice ,0302 clinical medicine ,Alzheimer Disease ,mental disorders ,medicine ,Pathology ,Animals ,Humans ,Amyloid beta-Peptides ,Microglia ,biology ,MEGF10 ,astrocytes ,phagocytosis ,Membrane Proteins ,Long-term potentiation ,Dystrophic synapses ,MERTK ,amyloid-beta ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Astrocytes ,Synapses ,biology.protein ,Alzheimer ,pathology ,030217 neurology & neurosurgery ,dystrophic synapses ,Astrocyte - Abstract
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., Research funding: Centro de Invesitgacion Biomedica en Red Enfermedades Neurodegenetativas (CIBERNED). Grant Numbers: CB06/05/0094, CB06/05/1116; Instituto de Salud Carlos III co‐financed by FEDER funds from European Union. Grant Numbers: PI18/01556, PI18/01557; Junta de Andalucia Consejería de Economía y Conocimiento co‐financed by Programa Operativo FEDER 2014‐2020. Grant Numbers: PY18‐RT‐2233, UMA18‐FEDERJA‐211, US‐1262734; La Marató‐TV3 Foundation. Grant Numbers: 20141430, 20141431, 20141432.
- Published
- 2020