Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment

Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing b-secretase is proposed to be critical for amyloid-beta (Ab) production. Here, we show that somatodendritic APP internalization in primary rodent neurons is not blocked by inhibiting dynamin or mutating the YENPTY motif, in contrast to non-neuronal cell lines. These phenomena, confirmed in induced human neurons under dynamin inhibition, occur during basal conditions and chemical long-term-depression stimulus, pointing to a clathrin-independent internalization pathway for somatodendritic APP. Mutating the YENPTY motif does not alter APP recycling, degradation, or endolysosomal colocalization. However, both dynamin inhibition and the YENPTY mutant significantly decrease secreted Ab in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Ab. Interestingly, like APP, somatodendritic low-density lipoprotein receptor (LDLR) internalization does not require its CME motif. These results highlight intriguing differences in neuronal internalization pathways and refine our understanding of Ab production and secretion.

Automated summary

In contrast to non-neuronal cell lines, inhibition of dynamin or mutation of the YENPTY motif does not block the internalization of amyloid precursor protein (APP) in primary rodent neurons. This clathrin-independent internalization pathway for somatodendritic APP occurs during basal conditions and chemical long-term-depression stimulus. Mutating the YENPTY motif does not affect APP recycling, degradation, or endolysosomal colocalization, but both dynamin inhibition and the YENPTY mutant significantly decrease secreted amyloid-beta (Ab) in neurons, suggesting that internalized APP may not be a major source of Ab. Intriguingly, somatodendritic low-density lipoprotein receptor (LDLR) internalization also does not require its clathrin-/dynamin-mediated endocytosis motif.