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Amyloid beta oligomers modulate neuronal autophagy through the primary cilium

View ORCID ProfileOlatz Pampliega, View ORCID ProfileFederico N. Soria, View ORCID ProfileNarayana Pineda-Ramírez, View ORCID ProfileErwan Bezard
doi: https://doi.org/10.1101/2021.06.02.446758
Olatz Pampliega
1Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33076, Bordeaux, France
2Centre National de la Recherche Scientifique, IMN, UMR 5293, 33076, Bordeaux, France
3Achucarro Basque Center for Neuroscience, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain
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  • For correspondence: olatz.pampliega@achucarro.org
Federico N. Soria
1Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33076, Bordeaux, France
2Centre National de la Recherche Scientifique, IMN, UMR 5293, 33076, Bordeaux, France
3Achucarro Basque Center for Neuroscience, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain
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Narayana Pineda-Ramírez
4Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Ciudad de México, 14269, México
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Erwan Bezard
1Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33076, Bordeaux, France
2Centre National de la Recherche Scientifique, IMN, UMR 5293, 33076, Bordeaux, France
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ABSTRACT

The major neurodegenerative diseases, like Alzheimer’s disease (AD), accumulate neuropathogenic proteins that compromise autophagic function. In AD, autophagy contributes to intracellular APP processing and amyloid beta (Aβ) generation by mutant presenilin-1 (PS1). However, how extracellular soluble Aβ oligomers (Aβo) impact intracellular autophagy is not well understood. The primary cilium (PC), a signaling organelle on the surface of mature neurons and glia, is able to bind Aβ. Since PC signaling pathways knowingly modify autophagy in non-brain cells, we here investigated the role of neuronal PC in the modulation of autophagy during acute extracellular Aβo overload. Our results show that, in vivo, recombinant Aβo require the presence of neuronal PC to modulate early autophagy and to induce the accumulation of autophagic vacuoles in an age-dependent manner. We show that activated Akt mediates these effects in an age-dependent manner, and that ciliary p75NTR receptor is required to block autophagy by Aβo. These findings demonstrate that neuronal PC in the adult brain participates in the deleterious effects mediated by soluble Aβo. The PC should therefore be considered as a target organelle to modulate autophagy for the treatment of neurodegenerative diseases.

Highlights

  • Aβo requires the neuronal PC to impair learning in young and old mice.

  • Autophagy in whole hippocampus differs from autophagy response in hippocampal neurons.

  • Aβo induce autophagolysosome accumulation through primary cilia- and age-dependent Akt phosphorylation.

Competing Interest Statement

Erwan Bezard owns equity stake in Motac holding Ltd and receives consultancy payments from Motac Neuroscience Ltd. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 02, 2021.
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Amyloid beta oligomers modulate neuronal autophagy through the primary cilium
Olatz Pampliega, Federico N. Soria, Narayana Pineda-Ramírez, Erwan Bezard
bioRxiv 2021.06.02.446758; doi: https://doi.org/10.1101/2021.06.02.446758
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Amyloid beta oligomers modulate neuronal autophagy through the primary cilium
Olatz Pampliega, Federico N. Soria, Narayana Pineda-Ramírez, Erwan Bezard
bioRxiv 2021.06.02.446758; doi: https://doi.org/10.1101/2021.06.02.446758

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