Amyloid beta oligomers modulate neuronal autophagy through the primary cilium

The major neurodegenerative diseases, like Alzheimers disease (AD), accumulate neuropathogenic proteins that compromise autophagic function. In AD, autophagy contributes to intracellular APP processing and amyloid beta (A{beta}) generation by mutant presenilin-1 (PS1). However, how extracellular soluble A{beta} oligomers (A{beta}o) 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 A{beta}. 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 A{beta}o overload. Our results show that, in vivo, recombinant A{beta}o 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 A{beta}o. These findings demonstrate that neuronal PC in the adult brain participates in the deleterious effects mediated by soluble A{beta}o. The PC should therefore be considered as a target organelle to modulate autophagy for the treatment of neurodegenerative diseases. HighlightsO_LIA{beta}o requires the neuronal PC to impair learning in young and old mice. C_LIO_LIAutophagy in whole hippocampus differs from autophagy response in hippocampal neurons. C_LIO_LIA{beta}o induce autophagolysosome accumulation through primary cilia- and age-dependent Akt phosphorylation. C_LI