Neurosecretases provide strategies to treat sporadic and familial Alzheimer disorders

Abstract

Recent discoveries on neurosecretases and their trafficking to release fibril-forming neuropeptides or other products, are of interest to pathology, cell signaling and drug discovery. Nomenclature arose from the use of amyloid precursor protein (APP) as a prototypic type-1 substrate leading to the isolation of β-secretase (BACE), multimeric complexes (γ-secretase, γ-SC) for intramembranal cleavage, and attributing a new function to well-characterized metalloproteases of the ADAM family (α-secretase) for normal APP turnover. While purified α/β-secretases facilitate drug discovery, γ-SC presents greater challenges for characterization and mechanisms of catalysis. The review comments on links between mutation or polymorphisms in relation to enzyme mechanisms and disease.The association between lipoprotein receptor LRP11 variants and sporadic Alzheimer's disease (SAD) offers scope to integrate components of pre- and post-Golgi membranes, or brain clathrin-coated vesicles within pathways for trafficking as targets for intervention. The presence of APP and metabolites in brain clathrin-coated vesicles as significant cargo with lipoproteins and adaptors focuses attention as targets for therapeutic intervention. This overview emphasizes the importance to develop new therapies targeting neurosecretases to treat a major neurological disorder that has vast economic and social implications.