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

Area of Science:

• Molecular Biology
• Cell Biology
• Neuroscience

Background:

• Gamma-secretases are intramembrane-cleaving proteases crucial for cellular signaling and implicated in Alzheimer's disease (AD).
• Cells express heterogeneous gamma-secretase complexes containing homologous presenilins (PSEN1 and PSEN2).
• Understanding the functional significance of this heterogeneity is key to elucidating AD pathogenesis.

Purpose of the Study:

• To investigate the role of presenilin heterogeneity in gamma-secretase function and substrate specificity.
• To determine how PSEN2 localization influences amyloid-beta (Aβ) production and accumulation.
• To examine the impact of familial AD (FAD) mutations on gamma-secretase localization and Aβ generation.

Main Methods:

• Identification of a unique motif in PSEN2 responsible for its localization.
• Analysis of phosphorylation-dependent interactions with the AP-1 adaptor complex.
• Assessment of Aβ production and localization in cells expressing wild-type and mutant PSEN1/PSEN2.

Main Results:

• A unique motif in PSEN2 directs it to late endosomes/lysosomes via interaction with the AP-1 complex.
• PSEN2 selectively cleaves substrates in late endosomes/lysosomes, generating longer Aβ species.
• FAD-associated mutations in PSEN2 and a subset of PSEN1 mutants enhance the accumulation of longer Aβ in these acidic compartments.
• Gamma-secretase localization dictates substrate specificity and FAD mutations promote aggregation-prone Aβ42 accumulation intracellularly.

Conclusions:

• Intracellular localization of gamma-secretase complexes is critical for substrate specificity.
• FAD-causing mutations in PSEN1 and PSEN2 lead to increased accumulation of aggregation-prone Aβ42 in late endosomes/lysosomes.
• Localized intracellular reactions involving gamma-secretase play a significant role in Alzheimer's disease pathogenesis.