APP functions at the endomembrane system

APP695 overexpression in N2a cells retains APP in Golgi and ER, clusters FE65, and significantly lowers ATF4 protein levels, linking APP to FE65-dependent regulation.

• Why it matters: The mechanisms controlling FE65 regulation by APP and the downstream targets remain unclear, limiting understanding of how APP influences endomembrane function and related disease pathways.
• What they did: N2a cells were engineered for APP695 overexpression, while H4 cells used CRISPR-Cas9 deletion or mutation of APP; proteomics, immunoblotting, and immunofluorescence assessed FE65 localization and ATF4, alongside autophagy readouts.
• The result: APP overexpression impaired autophagy, while APP knockout rescued LC3 conversion; FE65 knockdown restored ATF4, and the Swedish mutant did not affect ER stress or autophagic flux but increased gamma-secretase cleavage of APP-CTFs.

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