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Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during AD progression. PDAPPJ20 mice—murine model of AD—exhibited an accumulation of the autophagy receptor p62 and ubiquitin+ aggregates in Iba1+ microglial cells close to amyloid deposits in the hippocampus. Moreover, cultured microglial BV-2 cells showed an enhanced autophagic flux during a 2-h exposure to fibrillar Aβ, which was decreased if the exposure was prolonged to 24 h, a condition analogous to the chronic exposure to Aβ in the human pathology. The autophagic impairment was also associated with lysosomal damage, depicted by membrane permeabilization as shown by the presence of the acid hydrolase cathepsin-D in cytoplasm and altered LysoTracker staining. These results are compatible with microglial exhaustion caused by pro-inflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3-positive autophagic vesicles accumulated in phagocytic CD68+ microglia in human AD brain samples, suggesting defective autophagy in microglia of AD brain. Our results indicate that the capacity of microglia to degrade Aβ and potentially other proteins through autophagy may be negatively affected as the disease progresses. Preserving autophagy in microglia thus emerges as a promising approach for treating AD.

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Abbreviations

Tg:

Transgenic PDAPPJ20 mice.

NTg:

Non-transgenic PDAPPJ20 mice.

Aβ:

Amyloid-β peptides

fAβ42:

Fibrilar Amloid-β 1–42 peptides

BAF:

Bafilomycin A1

PA:

Plaque associated

NPA:

Non-plaque associated

Veh:

Vehicle

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Acknowledgments

The authors especially thank Dr. Marcelo Schultz from FLENI for technical support with human tissue and Dr. Juan Bonifacino for generous help with reagents and manuscript edition.

Funding

This work was supported by Williams, René Barón, and Alberto J. Roemmers Foundations, ANPCyT PICT Grants 2013-2645, 2014-1168, 2016-1046, and 2016-1572, CONICET PIP Grant 2013–2015 and UBACyT 2018 Grant. CP, RMG, AV, MB, and SPA are recipients of CONICET Fellowships. AG and JP are recipients of ANPCyT Fellowships. AA, GS, MLK, JB, and FS are CONICET Researchers. The funding sources had no involvement in the study design nor the collection, analysis and interpretation of data.

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Authors and Affiliations

  1. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina

    Carlos Pomilio, Angeles Vinuesa, Jessica Presa, Amal Gregosa, Melisa Bentivegna, Juan Beauquis & Flavia Saravia

  2. Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IQUIBICEN, CONICET, Buenos Aires, Argentina

    Roxana M. Gorojod, Agustina Alaimo, Soledad Porte Alcon & Monica L. Kotler

  3. FLENI, Instituto de Investigaciones Neurológicas Dr Raúl Carrea, Buenos Aires, Argentina

    Miguel Riudavets & Gustavo Sevlever

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  1. Carlos Pomilio
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  2. Roxana M. Gorojod
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  3. Miguel Riudavets
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  4. Angeles Vinuesa
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  6. Amal Gregosa
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  9. Soledad Porte Alcon
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  11. Monica L. Kotler
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  12. Juan Beauquis
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  13. Flavia Saravia
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Correspondence to Flavia Saravia.

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Pomilio, C., Gorojod, R.M., Riudavets, M. et al. Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients. GeroScience 42, 613–632 (2020). https://doi.org/10.1007/s11357-020-00161-9

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