Fig. 1
From: Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors
Spatial regulation of non-amyloidogenic and amyloidogenic processing of APP. Dysregulated amyloid precursor protein (APP) trafficking and processing underlies the most prominent hallmark of disease in AD affected areas, represented by an abundance of Aβ soluble oligomers, fibrils and plaques. Non-amyloidogenic processing starts with APP shedding by ADAM10, mainly at the cell surface but as well in the trans-Golgi network [10]. Hereafter, the remaining carboxyterminal fragments (CTFs), C83, are processed by γ-secretase to produce harmless p3 peptides and an intracellular domain (inset a). In the amyloidogenic pathway (inset b for details), which occurs more dominantly in neurons, APP is cleaved first by BACE1 preferentially in endosomes. This endosomal encountering is spatially regulated as BACE1 and APP are found to follow distinct internalization itineraries, the former mediated through ARF6 and GGA3 [11]. C99 is further processed by γ-secretase in recycling and degradative endosomes. It is first cut at position 48 or 49 of the Aβ sequence (ε-cleavage), followed by a carboxypeptidase-like trimming every three amino acids. This results in the production of different Aβ peptides of which the longer ones, like Aβ42 and Aβ43, are more aggregation-prone. γ-Secretase assembly is thought to occur stepwise during ER-Golgi recycling [12]. Assembled PSEN1 complexes (PSEN1/γ) are active at the cell surface and in sorting/recycling endosomes, while PSEN2 complexes (PSEN2/γ) reside in late endosomes/lysosomes due to an aminoterminal sorting motif that selectively binds AP-1. PICALM may mediate internalization of PSEN1/γ, while CD2AP in neurons sorts APP into intraluminal vesicles of MVBs for degradation in lysosomes, instead of through secretase-mediated processing pathways. BIN1 intervenes in recycling BACE1 to the cell surface as well as to lysosomes. BACE1 and APP sorting between distinct compartments involves several other sorting proteins and adaptor complexes of which some are depicted in this figure: such as GGA1, SNX17, retromer and SorLA