UCLA researchers from the Department of Neurology have developed first-in-class small-molecule activators of NPEPPS that effectively lower pathological tau, offering a novel disease-modifying strategy for Alzheimer’s and other neurodegenerative disorders.
BACKGROUND: Neurodegenerative dementias such as Alzheimer’s Disease (AD) and progressive supranuclear palsy (PSP) affect over 55 million people worldwide, with no approved disease-modifying therapies. A hallmark of these conditions is the abnormal aggregation of the tau (MAPT) protein into neurofibrillary tangles, which strongly correlate with neuronal loss and cognitive decline. While multiple approaches have attempted to inhibit tau aggregation or expression, most have faced challenges in efficacy or safety, underscoring the urgent need for new mechanisms to reduce pathological tau burden in the brain.
INNOVATION: Researchers at UCLA led by Dr. Daniel Geschwind and Dr. Michael Jung have identified puromycin-sensitive aminopeptidase (NPEPPS) as a previously unrecognized endogenous tau-degrading enzyme through a genome-wide functional screen. The team has developed first-in-class small-molecule NPEPPS activators that enhance the enzyme’s natural ability to lower tau levels and engage two major neuroprotective mechanisms: direct proteolytic degradation and autophagy activation. Lead compounds demonstrate nanomolar potency and blood brain barrier penetration. Researchers used patient iPSC-derived neurons to show that NPEPPS activators reduce pathological phosphorylated tau species and rescue neuronal survival. In a pathological tau mouse model, post-symptomatic treatment with a lead compound markedly lowered cortical tau pathology and improved neuronal integrity, confirming in vivo efficacy. Further, crystallographic and ligand-protein docking studies have revealed specific binding interactions between NPEPPS and its activators, enabling structure-guided optimization. In summary, these findings define a new therapeutic strategy to lower tau levels by directly enhancing an endogenous neuroprotective pathway, rather than blocking tau production or aggregation.
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DEVELOPMENT-TO-DATE: UCLA researchers have developed over 140 analogues and demonstrated in vitro efficacy in human iPSC-derived neurons and in vivo efficacy in the hTauP301S mouse model with post-symptomatic dosing.
Related Papers (from the inventors only): A Genomic Screen for Modifiers of Tauopathy Identifies Puromycin-Sensitive Aminopeptidase as an Inhibitor of Tau-Induced Neurodegeneration. Karsten, Stanislav L. et al. Neuron, Volume 51, Issue 5, 549 – 560
KEYWORDS: Tauopathy, NPEPPS, Alzheimer’s disease, PSP, neurodegeneration, small-molecule activator, proteostasis, structure-activity relationship, autophagy, drug discovery, brain-penetrant compound
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