RT Journal Article
T1 Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease.
A1 Sanchez-Mico, Maria Virtudes
A1 Jiménez, Sebastián
A1 Gómez-Arboledas, Ángela
A1 Muñoz-Castro, Clara
A1 Romero-Molina, Carmen
A1 Navarro, Victoria
A1 Sánchez-Mejías, Elisabeth
A1 Núñez-Díaz, Cristina
A1 Sánchez-Varo, Raquel María
A1 Galea, Elena
A1 Dávila-Cansino, José Carlos
A1 Vizuete, Marisa
A1 Gutiérrez-Pérez, Antonia
A1 Vitorica Ferrández, Javier
K1 Alzheimer, Enfermedad de
K1 Astrocitos
K1 Amiloide
K1 Fagocitosis
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 Wiley
YR 2020
FD 2020-12-07
LK https://hdl.handle.net/10630/29421
UL https://hdl.handle.net/10630/29421
LA eng
NO Sanchez-Mico MV, Jimenez S, Gomez-Arboledas A, Muñoz-Castro C, Romero-Molina C, Navarro V, Sanchez-Mejias E, Nuñez-Diaz C, Sanchez-Varo R, Galea E, Davila JC, Vizuete M, Gutierrez A, Vitorica J. Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease. Glia. 2021 Apr;69(4):997-1011. doi: 10.1002/glia.23943. Epub 2020 Dec 7. PMID: 33283891.
NO This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI18/01556 (to J.V.) and PI18/01557 (to A.G.); by La Marató-TV3 Foundation grants 20141432 (to A.G.), 20141431 (to J.V.), and 20141430 (to E.G.); by CIBERNED (CB06/05/0094 to JV and CB06/05/1116 to A.G.); and by Junta de Andalucia Consejería de Economía y Conocimiento through grants US-1262734 (to J.V.), UMA18-FEDERJA-211 (to A.G.) and P18-RT-2233 (to A.G.) co-financed by Programa Operativo FEDER 2014-2020. M.S.M., C.M.C., C.R.M., and C.N.D. were supported by PhD fellowships from FPU (Spanish Ministry of Science, Innovation and Universities) and FPI (Junta de Andalucia) programs. RSV held a postdoctoral contract from Malaga University. We thank Sanofi (France) for the APP model used in this work.
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 20 ene 2026