Heterogeneity of the γ-Secretases

γ-secretase is an intramembrane protease complex whose four human assemblies are defined by combinatorial association of PSEN1 or PSEN2 with APH1A or APH1B together with nicastrin and PEN-2. Rather than being functionally equivalent, the four complexes are now increasingly appreciated to differ in proteolytic output, substrate access, and disease susceptibility in ways that have direct therapeutic implications. Biochemical, structural, and genetic evidence collectively demonstrate that γ-secretase heterogeneity is not incidental, but both functional and consequential. Each complex produces a distinct amyloid-β profile reflecting differences in processive trimming efficiency, with PSEN2-containing complexes generating more aggregation-prone species than their PSEN1 counterparts. These intrinsic biochemical differences are compounded by differential subcellular sorting, with PSEN1 being trafficked to the plasma membrane and PSEN2 complexes directed to the endolysosomal compartment, creating spatially segregated proteolytic environments with distinct substrate repertoires and pH conditions. Complex composition varies across CNS cell types and is dynamically regulated by inflammatory and lipid signals, adding a contextual layer that cannot be reduced to subunit identity alone. In disease, the divergent clinical profiles of PSEN1 and PSEN2 familial Alzheimer’s Disease mutations, the non-redundant roles of APH1B complexes, and the selective therapeutic window achieved by PSEN1-specific inhibition in T-cell acute lymphoblastic leukaemia demonstrate that these distinctions have real pathological and pharmacological consequences. The failure of indiscriminate γ-secretase inhibitors in clinical trials reflects the cost of treating a heterogeneous system as uniform. The mechanistic framework now available, spanning structural biology, proteomics, transcriptomics and isoform-selective pharmacology, provides the tools to do better. Realising the therapeutic potential of γ-secretase will require heterogeneity to become a design principle rather than an afterthought.