Neuropharmacology

Biography

Biography: Varghese John

Abstract

Alzheimer’s disease (AD) is characterized by the presence of amyloid-β (Aβ ) plaques in brain tissue. Aβ is generated by sequential cleavage of full-length amyloid precursor protein (APP) by β and γ secretase. In an alternative pathway, α secretase cleavage of APP produces the protein fragment sAPPα, known to have trophic effects which support synaptic maintenance and memory. Proteolytic cleavage of APP by the β secretase BACE1 (BACE) as the initial step in production of Aβ has been a major target of AD drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and traumatic brain injury (TBI), and is also associated with stroke due to cerebral amyloid angiopathy (CAA). Others have observed in cells that Aβ production is reduced in the presence of increased sAPPα (Obregon et al, Nat. Commun. 2012). We therefore performed studies to determine the mechanism and revealed for the first time that sAPPα is a potent endogenous direct inhibitor of the BACE enzyme, and that this inhibition is likely by an allosteric mechanism. Furthermore, using small-angle x-ray scattering (SAXS), we show that sAPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different conformational structure than sAPPα and, importantly, does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAPPα as a direct BACE inhibitor would lead to the design of new therapeutics targeting pathologies associated with overproduction of Aβ. In this regard, we have identified through screening a repurposed drug F03 used in the treatment of post-operative nausea and vomiting (PONV) that increases sAPPα in the brain and is currently in a Phase1b/2a clinical trial in Australia in subjects with MCI due to AD. Alzheimer’s disease (AD) is characterized by the presence of amyloid-β (Aβ ) plaques in brain tissue. Aβ is generated by sequential cleavage of full-length amyloid precursor protein (APP) by β and γ secretase. In an alternative pathway, α secretase cleavage of APP produces the protein fragment sAPPα, known to have trophic effects which support synaptic maintenance and memory. Proteolytic cleavage of APP by the β secretase BACE1 (BACE) as the initial step in production of Aβ has been a major target of AD drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and traumatic brain injury (TBI), and is also associated with stroke due to cerebral amyloid angiopathy (CAA). Others have observed in cells that Aβ production is reduced in the presence of increased sAPPα (Obregon et al, Nat. Commun. 2012). We therefore performed studies to determine the mechanism and revealed for the first time that sAPPα is a potent endogenous direct inhibitor of the BACE enzyme, and that this inhibition is likely by an allosteric mechanism. Furthermore, using small-angle x-ray scattering (SAXS), we show that sAPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different conformational structure than sAPPα and, importantly, does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAPPα as a direct BACE inhibitor would lead to the design of new therapeutics targeting pathologies associated with overproduction of Aβ. In this regard, we have identified through screening a repurposed drug F03 used in the treatment of post-operative nausea and vomiting (PONV) that increases sAPPα in the brain and is currently in a Phase1b/2a clinical trial in Australia in subjects with MCI due to AD.