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

• Published in: Cell reports (Cambridge) 2023-07, Vol.42 (7), p.112774-112774, Article 112774
• Main Authors: Aow, Jonathan, Huang, Tzu-Rung, Goh, Yeek Teck, Sun, Alfred Xuyang, Thinakaran, Gopal, Koo, Edward H.
• Format: Article
• Language: English
• Subjects: amyloid precursor protein; amyloid-beta; APP; Bace1; clathrin motif; CP: Cell biology; CP: Neuroscience; dynamin; internalization; somatodendritic compartment; β-secretase
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112774

Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) 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 Aβ in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Aβ. 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 Aβ production and secretion. [Display omitted] •Somatodendritic APP endocytosis does not require dynamin activity or the YENPTY motif•LDLR endocytosis also does not require its NPVY motif, suggesting APP is not unique•Both dynamin inhibition and the YENPTY mutant reduce Aβ production and secretion•Somatodendritic APP endocytosis can be decoupled from pathways that generate Aβ Aow et al. show that APP internalization in the neuronal somatodendritic compartment is clathrin/dynamin independent, suggesting the presence of specialized endocytic pathways in different neuronal compartments. Internalized somatodendritic APP does not appear to represent a major source of Aβ, indicating that neurons compartmentalize surface APP pools toward downstream processing pathways.