Fig. 1: Amyloidogenic and non-amyloidogenic processing of APP.
From: Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches
The amyloid precursor protein (APP) is synthesized in the endoplasmic reticulum (ER) and passes through the Golgi apparatus where it undergoes several post-translational modifications such as N- and O-glycosylations, sialylations, phosphorylations and sulfatations before reaching the plasma membrane (PM) in its mature form (mAPP). There, APP can be processed into two different pathways. A In physiological conditions, APP mainly follows the non-amyloidogenic pathway (green arrows), where it is cleaved by the α-secretase, producing secreted sAPPα fragment and membrane-anchored APP-CTF-α (C83), which is then cleaved by the γ-secretase generating secreted P3 fragment and APP intracellular domain (AICD) fragment. Under physiological conditions, APP is also marginally processed in the amyloidogenic pathway (red arrows), in which it is first internalized in endosomes and cleaved by the β-secretase generating sAPPβ fragment and membrane-anchored APP-CTF-β (C99). The latter is subsequently cleaved by the γ-secretase to generate Aβ and AICD (APP intracellular domain), or by the α-secretase to generate the C83 peptide. B In Alzheimer’s disease (AD), APP is mostly processed in the amyloidogenic pathway. It also accumulates and is processed in the intracellular compartments including the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), where secretases are also present. Secreted monomeric Aβ1-42 (moAβ1-42) peptide is prone to oligomerize (oAβ1-42) and generates extracellular amyloid plaques.
