Elucidating BACE1 as a potential target for treating Niemann-Pick type C disease
The β-secretase, known as β-site amyloid precursor protein cleavage enzyme 1 (BACE1), plays a central role in Alzheimer’s disease (AD) pathogenesis as it initiates the production of the toxic amyloid-β peptides (Aβ) that accumulate in the brains of AD patients. BACE1 has become a prime therapeutic target for lowering Aβ, and clinical development of BACE1 inhibitors is being intensely pursued as avenue for treatment of AD. Interestingly, a rare inherited - yet untreatable - lysosomal storage disorder Niemann-Pick type C (NPC) and AD have several key features in common, including accumulation of Aβ and the β-secretase generated C-terminal fragments of the β-amyloid precursor protein (APP) - CTFβ, hyperphosphorylation of tau, neurodegeneration, and altered cholesterol metabolism.In light with the recently discovered similarities between AD and NPC, the goal of this project is to elucidate the role of BACE1 in the pathogenesis of NPC and whether BACE1 may represent a novel target for treating/ameliorating NPC disease. Furthermore, NPC can serve as an innovative model in which understanding of a defect caused by a single gene/protein (NPC1/NPC2) may help us to dissect molecular details of a more complex Alzheimer’s disease. However, these two neurodegenerative disorders show different vulnerabilities of the brain regions such as hippocampus, which is the most affected in AD and spared in NPC disease, and the cerebellum, which is spared in AD but is primarily affected in NPC. Further studies of similarities and differences between AD and NPC are encouraged to increase our understanding of the molecular pathogenesis of these conditions, as well as our chances of finding disease-modifying therapies. Based on our recent finding that β-secretase (BACE1) cleavage of APP is enhanced in NPC, in this project we will analyze whether enhanced BACE1-proteolysis in NPC is specific for APP or could also be observed for other BACE1 substrates such as seizure protein 6 (Sez6) and seizure 6-like protein 1 (Sez6L1). Both proteins seem to be involved in synaptic (dys)function and neurodegeneration – characteristic features of both AD and NPC disease. We will also test whether enhanced BACE1-cleavage in NPC correlates with distinct regional/neuronal vulnerabilities, accumulation of Aβ and CTFβ, tau hyperphosphorylation, activation of astrocytes and microglia. Lastly, using BACE1-inhibitor we will determine whether targeting BACE1 could be considered as an alternative approach for treating/ameliorating NPC disease. These studies may indicate a novel role of BACE1 in NPC pathogenesis and the potential of BACE1-inhibition as a novel strategy for treating NPC.