Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool

Abstract

γ-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing γ-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer Aβ further. Moreover, a subset of FAD mutants in PSEN1, normally more broadly distributed in the cell, phenocopies PSEN2 and shifts its localization to late endosomes/lysosomes. Thus, localization of γ-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone Aβ42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.

Intramembrane proteases as drug targets

“…Moreover, the presenilin-1 and -2 complexes have different cellular localization. Because of its restricted presence in the late endosomes and lysosomes, the presenilin-2-containing c-secretase complex is the main source of the intracellular pool of toxic Ab-species [45]. Hence, selective inhibitors may help clarify the role of generating intracellular versus extracellular Ab.…”

“…Both presenilin and Aph-1 subunits come in two different forms (presenilin-1/presenilin-2 and Aph-1A/ Aph-1B), giving rise to four possible complexes. Recently, it has been shown that presenilin-2 containing complexes mainly reside in the late endosomes and lysosomes, whereas preselinin-1 complexes have a broader distribution, including at the cell membrane [45].…”

“…2C). A recent paper has shown that c-secretase with presenilin-2 is mainly located in the late endosomes and lysosomes, whereas c-secretase with presenilin-1 is present in the endocytic pathway and predominantly in the plasma membrane [45]. (B) Metallo-IMPs display histidine and aspartic acid residues in different transmembrane helices (TMs) in order to coordinate a divalent metal ion (Zn…”

Amyloid-β and lysozyme proteotoxicity in Drosophila : Beneficial effects of lysozyme and serum amyloid P component in models of Alzheimer’s disease and lysozyme amyloidosis

“…The presenilin proteins 1 and 2 (PS1 and PS2) can both act as the catalytic domain in γ-secretase (Shirotani et al, 2007). However, in contrast to PS1, which is present in many cellular compartments, PS2 contains a sorting sequence that guides it to late endosomes and lysosomes, where it contributes to the production of the intracellular pool of Aβ, producing mainly the longer Aβ 1-42 peptide (Sannerud et al, 2016). BACE1 activity is at its highest in an acidic environment, around pH 4.5, which can be found in the vesicles that are part of the endosomal-lysosomal pathway (Vassar, 1999).…”

Investigating Amyloid β toxicity in Drosophila melanogaste

“…Studies using C-terminal-specific antibodies against Aβ40 and Aβ42 have demonstrated that most of the intracellular Aβ observed is in the longer, more aggregation prone, form [134]. Recent work described a sorting signal in presenilin-2 (PS2) (part of the γ-secretase) that directs the protease to endolysosomal vesicles, where the processing of AβPP renders a pool of intracellular Aβ, enriched with Aβ42 [135]. Both in vitro and in vivo reports have displayed that the accumulation of intracellular Aβ precedes the build up of extracellular deposits [134] and AD transgenic mice studies have reported a correlation between levels of intracellular Aβ and Aβ-related synapse damage and memory impairment.…”