Amyloid beta oligomers modulate neuronal autophagy through the primary cilium
Preprint bioRxiv. 2021-06-02; :
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.HighlightsAβo 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.