Amyloid Precursor Protein Processing and Trafficking Dynamics

Amyloid precursor protein (APP) is a type I transmembrane glycoprotein that undergoes complex routing through the secretory and endocytic pathways of neurons and non-neuronal cells. Proteolytic processing of APP follows two principal routes: the non-amyloidogenic pathway, in which α-secretase cleaves within the Aβ domain to preclude amyloid formation, and the amyloidogenic pathway, in which sequential β- and γ-secretase cleavages generate amyloid-β (Aβ) peptides prone to aggregation. The localisation and convergence of APP with its secretases in subcellular compartments—such as the trans-Golgi network, early endosomes and late endosomes or lysosomes—critically regulate the balance between these pathways. Intracellular trafficking machinery, including adaptor proteins, retromer complexes and clathrin-dependent and ‑independent routes of endocytosis, governs APP’s residence time in these compartments and thus influences Aβ production. Post-translational modifications of APP, such as phosphorylation, glycosylation and ubiquitination, further modulate its sorting, cleavage and degradation. Familial Alzheimer’s disease mutations often perturb APP trafficking or its interaction with secretases, accelerating Aβ accumulation. Understanding the dynamic interplay between APP processing and intracellular transport is fundamental to deciphering Alzheimer’s disease mechanisms and for the development of strategies that selectively shift APP processing toward non-pathogenic outcomes.

Research from Nature Portfolio

Recent studies have demonstrated that targeted editing of the APP gene at its extreme C-terminus can rebalance its proteolytic fate. By applying CRISPR/Cas9 to introduce precise modifications in cell and animal models, researchers have shown that disruption of the C-terminal sequence attenuates APP interaction with β-secretase, thereby reducing pathogenic Aβ generation, while simultaneously enhancing α-secretase cleavage and the production of neuroprotective soluble APPα. This approach preserves the APP N-terminus and related homologues, avoids off-target effects and maintains normal neuronal physiology in vitro and in vivo. Mechanistic analysis reveals that the edited C-terminal region impairs the approximation of APP and BACE1 within endosomal compartments, providing proof of concept for a gene-editing strategy that selectively silences amyloidogenic APP processing without broad disruption of secretase functions.

Amyloid Precursor Protein Processing and Trafficking Dynamics publication trend

The graph below shows the total number of articles in amyloid precursor protein processing and trafficking dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloidogenic pathway: Sequential β- and γ-secretase cleavage of APP yielding Aβ peptides.

Non-amyloidogenic pathway: α-secretase cleavage of APP within the Aβ domain, preventing Aβ formation.

Endosomes: Membrane-bound organelles (early, recycling and late) central to protein sorting and trafficking.

Retromer complex: A multi-protein assembly that mediates the retrieval of cargo from endosomes to the trans-Golgi network.

YENPTY motif: A cytoplasmic internalisation signal in APP that interacts with adaptor proteins to regulate endocytosis.

CRISPR/Cas9 editing: A gene-editing technique used here to introduce targeted mutations in the APP C-terminus.

BACE1 (β-secretase): The aspartyl protease that initiates amyloidogenic APP cleavage in endosomal compartments.

Presenilin-1: The catalytic subunit of γ-secretase responsible for the final cleavage that releases Aβ peptides.

References

1. Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment. Cell Reports (2023).
2. APP-BACE1 Interaction and Intracellular Localization Regulate Aβ Production in iPSC-Derived Cortical Neurons. Cellular and Molecular Neurobiology (2023).
3. Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations. Biochemical Journal (2024).
4. CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nature Communications (2019).